Novel carbostyril derivatives

ABSTRACT

Novel carbostyril derivatives having platelet aggregation inhibitory action, antiinflamatory action, antiulcer action, vasodilatory action and phosphodiesterase inhibitory action and are useful for preventing or curing thrombus, arteriosclerosis, hypertension, asthma and other like diseases, and also useful as an antiinflamatory or anti-ulcer agent, represented by the formula ##STR1## wherein R 1  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, phenyl-C 1-4  alkyl-; R 2  is hydrogen, a halogen atom, hydroxy, phenyl-C 1-4  alkoxy; R 3  is hydrogen, hydroxy, C 1-4  alkyl; R 4  is C 3-8  cycloalkyl, substituted or unsubstituted phenyl, C 3-8  cycloalkyl-C 1-4  alkyl, 2-(3,4-dimethoxyphenyl)-ethyl, R 5  is hydrogen, C 1-8  alkyl, C 2-4  alkenyl, phenyl, C 3-8  cycloalkyl, phenyl-C 1-4  alkyl, C 3-8  cycloalkyl-C 1-4  alkyl, m is an integer of 1 - 3, l and n which may be same or different, and are respectively 0 or an integer of 1 - 7 and the sum of l and n is not exceeding 7, the carbon-carbon bond at 3- and 4-positions in the carbostyril skelton is either single or double bond.

This is a continuation, of application Ser. No. 914,589, filed June 9, 1978, now abandoned.

The present invention relates to novel carbostyril derivatives.

The compounds provided according to the present invention are novel carbostyril derivatives and salts thereof represented by the following general formula: ##STR2## wherein R¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms or a phenylalkyl group formed from combination of a phenyl group and an a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms, R² is a hydrogen atom, a halogen atom, a hydroxy group or a phenylalkoxy group formed from combination of a phenyl group and an alkyleneoxy group having 1 to 4 carbon atoms, R³ is a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R⁴ is a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted phenyl group, a cycloalkylalkyl group formed from combination of a cycloalkyl group having 3 to 8 carbon atoms and an alkylene group having 1 to 4 carbon atoms, or 2-(3,4-dimethoxyphenyl)ethyl group, R⁵ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a phenyl group, an unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a phenylalkyl group formed from combination of a substituted or unsubstituted phenyl group and an alkylene group having 1 to 4 carbon atoms, or a cycloalkylalkyl group formed from combination of a cycloalkyl group having 3 to 8 carbon atoms and an alkylene group having 1 to 4 carbon atoms; m is an integer of 1 to 3, and l and n, which may be the same or different, and are respectively 0 or an integer of 1 to 7, and the sum of l and n is not exceeding 7; the carbon-carbon bond at 3- and 4-positions in the carbostyril skelton is either single or double bond.

The compounds of the present invention have a platelet aggregation inhibitory action, antiinflamatory action, antiuler action, vasodilatory action and phosphodiesterase (PDE) inhibitory action and are useful for preventing or curing thrombus, arteriosclerosis, hypertension, asthma and other like diseases, and also useful as an antiinflamatory or anti-ulcer agent.

In the general formula (1), as to the alkyl group having 1 to 4 carbon atoms represented by R¹ and R³ may be more definitely specified as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group or the like. As to the alkyl group having 1 to 8 carbon atoms represented by R⁵ may be more definitely specified as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 2-methylbutyl group, hexyl group, isohexyl group, 2-ethylbutyl group, heptyl group, 3-methylhexyl group or octyl group. As to the alkenyl group having 2 to 4 carbon atoms represented by R¹ and R⁵ may be definitely specified as vinyl group, allyl group, isopropenyl group or 2-butenyl group. As to the phenylalkyl group represented by R¹ may be a phenylalkyl group formed from combination of a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms and a phenyl group, and examples of such phenylalkyl group are benzyl group, 2-phenylethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and 1,1-dimethyl-2-phenylethyl group. The halogen atom represented by R² may be chlorine atom, bromine atom, iodine atom or fluorine atom. The phenylalkoxy group represented by R² may be the one formed from combination of the above-said phenylalkyl group and an oxygen atom, and examples of such phenylalkoxy group include benzyloxy group, 2-phenylethoxy group, 1-phenylethoxy group, 3-phenylpropoxy group, 4-phenylbutoxy group and 1,1-dimethyl-2-phenylethoxy group. The unsubstituted cycloalkyl group having 3 to 8 carbon atoms represented by R⁴ and R⁵ include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group. The substituted cycloalkyl group having 3 to 8 carbon atoms represented by R⁴ may be the above-said type of cycloalkyl group which has undergone substitution with one or two same or different substituents such as for example an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group; an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy group; a halogen atom such as chlorine atom, bromine atom, iodine atom or fluorine atom; an alkanoylamino group such as acetylamino, propionylamino, butyrylamino or isobutyrylamino group; an alkanoyloxy group such as acetyloxy, propionyloxy, butyryloxy or isoburyloxy group; an alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl group; an alkanoyl group such as acetyl, propionyl, butyryl or isobutyryl group; an alkylcarbamoyl group such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N,N-diethylcarbamoyl or N-methyl-N-propylcarbamoyl group; an alkylamino group such as N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N-ethylamino, N-isopropylamino, N-methyl-N-ethylamino or N,N-dibutylamino group; a nitro group, a carboxy group, a hydroxyl group, an aminosulfonyl group, a carbamoyl group or an amino group. The substituted phenyl group represented by R⁴ may be one which has undergone substitution with one or two substituent groups such as above-mentioned. The cycloalkylalkyl groups represented by R⁴ and R⁵ may be those formed from combination of a cycloalkyl group having 3 to 8 carbon atoms and a straight-chain or branched alkylene group having 1 to 4 carbon atoms, and as examples of such cycloalkylalkyl groups, one may cite the following: 4-cyclohexylbutyl group, 2-cyclopentylethyl group, cyclohexylmethyl group, 2-cyclopentylpropyl group, 3-cyclohexylpropyl group, cyclopentylmethyl group, 2-cyclohexylethyl group, 2-cyclohexylpropyl group, 2-cycloheptylethyl group, 3-cyclobutylpropyl group, 1,1-dimethyl-2-cyclohexylethyl group, and 1-methyl-2-cyclopentylethyl group. The substituted or unsubstituted phenylalkyl group represented by R⁵, may be any of the above-mentioned phenylalkyl groups or those phenylalkyl groups which have, as substituent, one or two above-said alkoxy groups having 1 to 4 carbon atoms on the phenyl ring, and more definite examples of such phenylalkyl groups are 4-ethoxybenzyl, 2-(3,4-dimethoxyphenyl)ethyl, 1-(3,5-dimethoxyphenyl)ethyl, 3-(2-butoxyphenyl)propyl, 4-(3,4-dimethoxyphenyl)butyl and 1,1-dimethyl-2-(3,4-diethoxyphenyl)ethyl groups.

Listed below are the representative examples of the compounds provided according to this invention.

6-(N-Allyl-N-cyclopentylaminocarbonylmethoxy)-carbostyril

6-(N-Methyl-N-cycloheptylaminocarbonylmethoxy)-carbostyril

6-(N-Methylanilinocarbonylmethoxy)-3,4-dihydrocarbostyril

6-[2-(N-Ethyl-N-cyclooctylaminocarbonyl)-ethoxy]carbostyril

6-[2-(N-Allyl-N-cycloheptylaminocarbonyl)-ethoxy]-3,4-dihydrocarbostyril

6-[3-(N-Cycloheptylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

6-[3-(N-Allyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

6-[3-(N-Ethyl-N-cyclohexylaminocarbonyl)-propoxy]-3,4-dihydrocarbostyril

6-[3-(N-Butyl-N-cyclooctylaminocarbonyl)-propoxy]carbostyril

6-[3-(N-Methyl-N-cyclooctylaminocarbonyl)-propoxy]carbostyril

6-[3-(N-Butyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

6-[3-(o-Chloroanilinocarbonyl)propoxy]carbostyril

6-[3-(p-Methoxyanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril

6-[3-(m-Hydroxyanilinocarbonyl)propoxy]carbostyril

6-[3-(N-Ethylanilinocarbonyl)propoxy]carbostyril

6-[3-(N,N-Diphenylaminocarbonyl)propoxy]carbostyril

6-[3-(N-Methyl-o-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril

6-[3-(N,N-Dicyclohexylaminocarbonyl)propoxy]-carbostyril

6-[3-(N-Cyclopentyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

6-[3-(N-Cyclohexylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril

6-[4-(N-Ethyl-N-cyclohexylaminocarbonyl)-butoxy]carbostyril

6-[4-(N-Methylanilinocarbonyl)butoxy]-3,4-dihydrocarbostyril

6-[4-(o,o-Dimethylanilinocarbonyl)butoxy]-carbostyril

6-[5-(N-Methyl-N-cyclohexylaminocarbonyl)-pentyloxy]carbostyril

6-[5-(N-Cyclohexylanilinocarbonyl)pentyloxy]-carbostyril

6-[6-(N-Methyl-N-cyclohexylaminocarbonyl)-hexyloxy]-3,4-dihydrocarbostyril

6-[6-(N-Ethylanilinocarbonyl)hexyloxy]carbostyril

5-(N-Methyl-N-cycloheptylaminocarbonylmethoxy)-3,4-dihydrocarbostyril

5-[2-(N-Methyl-N-cyclohexylaminocarbonyl)-ethoxy]carbostyril

6-[8-(N-Ethyl-N-cyclohexylaminocarbonyl)-octyloxy]carbostyril

5-[3-(N-Allyl-N-cyclopentylaminocarbonyl)-propoxy]carbostyril

5-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

5-[3-(N-Propylanilinocarbonyl)propoxy]-carbostyril

5-[3-(N,N-Dicyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

5-[4-(N-Methyl-N-cyclohexylaminocarbonyl)-butoxy]-3,4-dihydrocarbostyril

5-[5-(N-Methyl-N-cyclohexylaminocarbonyl)-pentyloxy]carbostyril

7-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

7-[3-(N-Ethylanilinocarbonyl)propoxy]carbostyril

8-[3-(N-Ethyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

6-[3-(N-Octyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

5-[3-(N-Heptyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostryil

6-{3-[N-Cyclohexyl-N-(2-phenylethyl)-aminocarbonyl]propoxy}carbostyril

5-(o-Chloro-p-nitroanilinocarbonylmethoxy)-3,4-dihydrocarbostyril

6-[3-(o-Carboxyanilinocarbonyl)propoxy]-carbostyril

6-[3-(N-Ethyl-p-aminosulfonylanilinocarbonyl)-propoxy]carbostyril

6-[3-(N-Methyl-o-carbamoylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Phenyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy}carbostyril

6-{1-[o-(N-Methylcarbamoyl)anilinocarbonyl]-ethoxy}carbostyril

5-[1-(o-Carboxyanilinocarbonyl)ethoxy]-3,4-dihydrocarbostyril

1-Allyl-5-[1-(p-methoxyanilinocarbonyl)-ethoxy]-3,4-dihydrocarbostyril

1-Ethyl-6-[3-(N-methylanilinocarbonyl)-propoxy]carbostyril

1-Benzyl-6-[3-(N,N-diphenylaminocarbonyl)-propoxy]carbostyril

6-[2-Methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

6-[2-Butyl-3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyl

6-[4-Methyl-5-(N-propyl-N-cyclohexylaminocarbonyl)heptyloxy]carbostyril

5-[2-Methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

8-[2-Methyl-3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

5-Chloro-6-[3-(N-ethyl-o-methylanilinocarbonyl)propoxy]carbostyril

5-Fluoro-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril

5-Chloro-6-[2-methyl-3-(N-methyl-N-cyclohexylamiocarbonyl)propoxy]-3,4-dihydrocarbostyril

5,6,7-Tribromo-8-[3-(N-methylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyril

5,6,7-Trichloro-8-[5-(N-ethyl-N-cyclohexylamino)pentyloxy]carbostyril

8-Bromo-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

8-Bromo-6-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

6,8-Dichloro-5-[3-(N-ethylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyril

5,7-Dichloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

5,7,8-Trichloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

8-Hydroxy-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

5-Benzyloxy-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

7-Hydroxy-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

5,8-Dihydroxy-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

1-(4-Phenylbutyl)-5-[3-(N-ethyl-N-cyclopropylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

1-(2-Butenyl)-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

6,8-Dichloro-1-methyl-5-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy]carbostyril

8-Hydroxy-1-ethyl-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

1-Methyl-7-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

5-{1-[N-Ethyl-N-(3-methylcyclohexyl)aminocarbonyl]propoxy}carbostyril

5-{3-[N-Methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Methyl-N-(3-hydroxycyclohexyl)-aminocarbonyl]propoxy}carbostyril

6-[3-(N-4-Methoxycyclohexylaminocarbonyl)-propoxy]-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(4-acetyloxycyclohexyl)-aminocarbonyl]propoxy}carbostyril

6-{2-Methyl-3-[N-methyl-N-(2-methylcyclohexyl)-aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

1-Benzyl-6-[3-(N-4-ethoxycycloheptylaminocarbonyl)propoxy]carbostyril

8-Hydroxy-5-{1-[N-methyl-N-(3-methylcyclohexyl)-aminocarbonyl]propoxy}carbostyril

5,6,8-Trichloro-6-{3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(2-hydroxy-5-methylcyclohexyl)-aminocarbonyl]propoxy}carbostyril

6-{3-[N-ethyl-N-(4-nitrocyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(2-carboxycyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Ethyl-N-(2-N-methylcarbamoylcyclohexyl)aminocarbonyl]propoxy}carbostyril

5-{3-[N-Methyl-N-(2-N,N-diethylcarbamoylcyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Ethyl-N-(2-carbamoylcyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Methyl-N-(4-chlorocyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Methyl-N-(3,4-dimethoxycyclohexyl)-aminocarbonyl]propoxy}carbostyril

6-{3-[N-Allyl-N-(4-aminosulfonylcyclohexyl)-aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(3-acetylcyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Methyl-N-(4-acetylaminocyclohexyl)-aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(4-N,N-dimethylaminocyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Methyl-N-(2,6-dimethylcyclohexyl)-aminocarbonyl]propoxy}carbostyril

6-{3-[N-ethyl-N-(2,5-dimethoxycyclohexyl)-aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(2,5-dichlorocyclohexyl)-aminocarbonyl]propoxy}carbostyril

6-{3-[N-Cyclohexylmethyl-(2-chlorocyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Methyl-N-(2-aminocyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-[2-Hydroxy-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril

5-[2-Hydroxy-3-(N-ethyl-p-methylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyril

6-[2-Hydroxy-3-(N-methylanilinocarbonyl)propoxy]-carbostyril

1-Ethyl-6-[2-hydroxy-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril

6-{3-[N-Methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Allyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Benzyl-N-(2-3',4'-dimethoxyphenylethyl)-aminocarbonyl]propoxy}carbostyril

6-{3-[N-Phenyl-N-(2-3',4'-dimethoxyphenylethyl)-aminocarbonyl]propoxy}carbostyril

6-{3-[N-Cyclohexyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyril

6-{2-Methyl-3-[N-ethyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyril

5-Chloro-6-{3-[N-methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyril

1-Methyl-6-{3-[N-methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

8-Hydroxy-5-{3-[N-methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Octyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy}carbostyril

6-{3-[N-Heptyl-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril

6-{3-[N-Octyl-N-(2-chlorocyclohexyl)aminocarbonyl]propoxy}carbostyril

6-[3-(N-Cyclohexyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyril

6-{3-[N-(2-Cyclopentyl-1-methylethyl)aminocarbonyl]propoxy}carbostyril

6-{2-[N-(2-Cyclopentylethyl)aminocarbonyl]-ethoxy}-3,4-dihydrocarbostyril

The compounds of this invention can be produced according to various processes such as for example expressed by the following reaction process formula-1 and reaction process formula-2: ##STR3## wherein X is a halogen atom, and R¹, R², R³, R⁴, R⁵, m, l, n and carbon-carbon bond at 3- and 4-positions in the carbostyril skeleton are all same as defined above.

The starting materials used in this invention, that is, hydroxycarbostyril derivatives represented by the general formula (2), haloamide represented by the general formula (3), carboxyalkoxycarbostyril derivatives represented by the general formula (4) and amines represented by the general formula (5) may be all either known compounds or novel compounds and can be prepared according to the reaction process formulae -5 to -11 shown later.

The process expressed by the reaction process formula-1 is an ordinary method for carrying out a dehydrohalogenation reaction of a hydroxycarbostyril derivative represented by the general formula (2) with a haloamide represented by the general formula (3). The halogen atom in the haloamide may be bromine, chlorine or iodine atom. This dehydrohalogenation reaction is accomplished by using a basic compound as dehydrohalogenating agent. The basic compound used in said reaction may be selected from a wide variety of known basic compounds including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate, etc.; alkali metals such as sodium, potassium, etc.; alcoholates such as sodium methylate, sodium ethylate, etc.; and organic bases such as triethylamine, pyridine, N,N-dimethylaniline, etc. The above reaction can be carried out in the absence or presence of a solvent. The solvent used in this reaction may be of any known inert type which gives no adverse effect to the reaction. Among the examples of such solvent are alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; ketones such as acetone, methyl ethyl ketone, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; esters such as methyl acetate, ethyl acetate, etc.; and aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide. It is advantageous to carry out the said reaction in the presence of a metallic iodide such as sodium iodide or potassium iodide. The ratio of amount of hydroxycarbostyril derivative (2) with haloamide (3) in the above method is not subject to any specific restriction and may be suitably selected from a wide range, but usually, it is desirable that the latter is used in equimolar to 5 times the molar quantity, preferably equimolar to double the molar quantity of the former. The reaction temperature is also not subject to any particular definition, but the reaction is usually carried out at room temperature to 200° C., preferably at 50° to 150° C. The reaction time is usually 1 to 30 hours, preferably 1 to 15 hours.

The process expressed by the reaction process formula-2 is a method for reacting a carboxyalkoxycarbostyril derivative represented by the general formula (4) with an amine represented by the general formula (5) according to an ordinary mode of amide bond forming reaction. The compound of the general formula (4) used in the invention may be substituted by a compound in which the carboxy groups were activated. It is also possible to use a compound having the activated amino groups in place of the amine represented by the general formula (5). The known amide bond forming reaction conditions may be easily applied to the practice of the amide bond forming reaction in this invention. For instance, the following methods are available for said reaction: (a) mixed acid anhydride method, thus on alkylhalocarboxylic acid is reacted with a carboxylic acid (4) to form a mixed acid anhydride and the latter is further reacted with an amine (5); (b) active ester method, thus a carboxylic acid (4) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinic acid imidoester, 1-hydroxybenzotriazole ester or the like and then such active ester is reacted with an amine (5); (c) carbodiimide method, thus an amine (5) is reacted with a carboxylic acid (4) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc., to effect dehydration condensation; (d) other methods, thus a carboxylic acid (4) is converted into a carboxylic acid anhydride with a dehydrating agent such as acetic acid anhydride and then the carboxylic acid anhydride is reacted with an amine (5); high pressure and high temperature method, thus an amine (5) is reacted with an ester of a carboxylic acid (4) with a lower alcohol under a high pressure and high temperature condition; a method of reacting an amine (5) is reacted with an acid halide of a carboxylic acid (4), namely a carboxylic acid halide. Most preferrable method among these methods is mixed acid anhydride method. The alkylhalocarboxylic acid used in the mixed acid anhydride method may be for example methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate or the like. The mixed acid anhydride may be obtained by an usual Schotten-Baumann reaction, and this substance, usually without isolation, is reacted with an amine (5) to produce the compound of the present invention. The Schotten-Baumann reaction is carried out in the presence of a basic compound. Such basic compound may be commonly used for the Schotten-Baumann reactions and may be for example an organic base such as triethylamine, trimethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, etc.; or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, etc. Said reaction is usually carried out at a temperature within the range of -20° to 100° C., preferably 0° to 50° C., for the period of 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and an amine (5) is carried out at a temperature of -20° to 150° C., preferably 10° to 50° C., for the period of 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method is usually carried out in a solvent. Any type of solvent commonly used in the mixed acid anhydride method may be employed, for example halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc.; esters such as methyl acetate, ethyl acetate, etc.; and aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide, hexamethylphosphoric acid triamide, etc. In this method, the carboxylic acid (4), alkylhalocarboxylic acid and amine (5) are usually used in the equimolar ratio to each other, but the alkylhalocarboxylic acid and amine (5) may be used in 1 to 1.5 times the molar quantity of the carboxylic acid (4).

The compounds of the invention can be also produced according to the processes expressed by the following reaction process formula-3 and reaction process formula-4. A compound of the general formula (1b) can be obtained by dehydrogenating a compound of the general formula (1a), while a compound of the general formula (1a) can be obtained by reducing a compound of the general formula (1b). A compound of the general formula (1d) can be produced from a dehydrohalogenation reaction of a compound of the general formula (1c) with a compound of the general formula (6). ##STR4## wherein R¹ ' is an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 4 carbon atoms or a phenylalkyl group, and R¹, R², R³, R⁴, R⁵, m, l, n, X and carbon bond at 3- and 4-positions in the carbostyril skeleton are same as defined above. However, R² of the compound (1b) used as starting material for the reduction reaction in reaction process formula-3 is a hydrogen atom or a hydroxy group.

In reaction process formula-3, the dehydrogenation of a compound of the general formula (1a) can be accomplished according to an usual method by subjecting the compound to a dehydrogenation reaction in a suitable solvent by using an oxidizing agent. As to oxidizing agents which may be used in this reaction are, for example, benzoquinones such as 2,3-dichloro-5,6-dicyanobenzoquinone (hereinafter referred to as DDQ), chloranil (2,3,5,6-tetrachlorobenzoquinone), etc.; metallic catalysts such as selenium dioxide, palladium carbon, palladium black, platinum oxide, Raney nickel, etc.; and brominating agents such as N-bromosuccinimide, bromine, etc. As solvents which may be used in this reaction are, ethers such as dioxane, tetrahydrofuran, 2-methoxyethanol, dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, etc.; alcohols such as butanol, amyl alcohol, hexanol, etc., and aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. This reaction is usually carried out at the temperature within the range of room temperature to 300° C., preferably 50° to 200° C., for the period of 1 hour to 2 days, preferably 1 to 20 hours. In case of using a benzoquinone or brominating agent as oxidating agent, it is usually used in an amount of 1 to 5 times, preferably 1 to 2 times the moles of compound (1a), and in case of using a metallic catalyst as oxidating agent, it may be used in an ordinary amount employed in an usual catalytic reaction.

In the reaction process formula-3, the catalytic reduction of the compound (1b) can be accomplished in the usual way by hydrogenating said compound in a suitable solvent by using a catalyst. Any known type of catalysts may be used for this reduction reaction. As examples thereof, one may cite platinum catalysts such as platinum wire, platinum plate, platinum sponge, platinum black, platinum oxide, colloidal platinum, etc.; palladium catalysts such as palladium sponge, palladium black, palladium oxide, palladium-barium sulfate, palladium-barium carbonate, palladium carbon, palladium silica gel, colloidal palladium, etc.; platinum group catalysts such as asbestos-filled rhodium, iridium, colloidal rhodium, ruthenium catalysts, colloidial iridium, etc., nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, nickel catalysts produced from thermal decomposition of nickel formate, nickel boride, etc.; cobalt catalysts such as reduced cobalt, Raney cobalt, Urushibara cobalt, etc; iron catalysts such as reduced iron, Raney iron, etc.; copper catalysts such as reduced copper, Raney copper, Ullmann copper, etc.; and other metallic catalysts such as zinc. The solvent used in the above reaction may be, for example, a lower alcohol (such as methanol, ethanol, isopropanol, etc.), water, acetic acid, an acetic acid ester (such as methyl acetate, ethyl acetate, etc.), ethylene glycol, an ether (such as diethyl ether, tetrahydrofuran, dioxane, etc.), an aromatic hydrocarbon (such as benzene, toluene, xylene, etc.), a cycloalkane (such as cyclopentane, cyclohexane, etc.), an n-alkane (such as n-hexane, n-pentane, etc.). The reaction is carried out under normal hydrogen pressure or under pressure, preferably under 1 to 20 atm., and at the temperature between room temperature and boiling point of the solvent, preferably between room temperature and 100° C.

In the reaction process formula-4, the reaction between the compound (1c) and the compound (6) is carried out by reacting the compound (1c) in the form of an alkali metal salt with the compound (6). The reaction for obtaining an alkali metal salt from the compound (1c) is conducted in the presence of an alkali metal compound. The alkali metal compound used here may be, for example, a metallic hydride such as sodium hydride, potassium hydride, etc.; an alkali metal such as metallic sodium, or sodium azide. This reaction is usually carried out in a solvent. Among the solvents usable in this reaction are aromatic hydrocarbon solvents such as benzene, toluene, xylene, etc.; ether solvents such as diethyl ether, 1,2-dimethoxyethylene, dioxane, etc.; and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.; but the last-said aprotic polar solvents are most preferable. The alkali metal compound is usually used in an amount of 1 to 5 times, preferably 1 to 3 times the molar quantity of the compound (1c). The reaction temperature may be suitably selected from a wide range, usually 0° to 200° C., but the reaction advances most advantageously within the range of room temperature to 50° C. This reaction provides a compound (1c) where the nitrogen at 1-position has been substituted with an alkali metal. The reaction for obtaining the compound (1d) from an alkali metal salt of the above-obtained compound (1c) with the compound (6) is a condensation reaction. This condensation reaction may be accomplished easily in a usual way, but generally this reaction advances in a most preferred mode by reacting both compounds at room temperature in a solvent, for example, dimethylformamide. The amount of the compound (6) used may be suitably selected from a wide range, but usually it is desirably used in an amount of 1 to 5 times, most preferably 1 to 3 times the moles of the alkali metal salt of the compound (1c).

The process of the present invention is not limited to the above-described two-stage operation; it is of course possible to carry out the reaction by introducing the three compounds, that is, the compounds of the general formulae (1c) and (6) and said alkali metal compound simultaneously into the reaction system, and in this case, too, it is possible to obtain the compound of the present invention through the same course of reaction as said above.

Among the compounds represented by the general formula (2) used as the starting material in the present invention, the compound (2b) having a halogen atom as to R² can be easily obtained by halogenating the compound (2a) (known compound) which is among the compounds represented by the general formula (2) and which has a hydrogen atom as to R², as expressed by the following reaction process formula-5. ##STR5## wherein X is a halogen atom, and R¹, m and carbon bond at 3- and 4-positions in the carbostyril skeleton are as defined above.

The halogenation reaction of the compound (2a) can be accomplished advantageously by using a known halogenating agent. Examples of such halogenating agent are fluorine, chlorine, bromine, iodine, xenon difluoride, sulfuryl chloride, sodium hypochlorite, hypochlorous acid, hypobromous acid, bleaching powder, etc. The amont of the halogenating agent may be suitably selected from a wide range in accordance with the number of the halogen atoms to be introduced into the compound (2a). In case of introducing one halogen atom, said halogenating agent is usually used in an amount of 1 to 2 times, preferably 1 to 1.5 times the molar quantity of the compound (2a), and in case of introducing two halogen atoms, said halogenating agent is used in an amount of 1.5 times the moles to large excess, preferably 2 to 3 times the moles of the compound (2a). In case of introducing three halogen atoms, said agent is used in an amount of 2.5 times the moles to large excess, preferably 3 to 5 times the moles of the compound (2a). Such halogenation reaction is usually conducted in a suitable solvent such as for example water, methanol, ethanol, chloroform, carbon tetrachloride, acetic acid or a mixture thereof. The reaction temperature is not subject to any particular definition and can be suitably selected from a wide range, but usually the reaction is carried out at the temperature of around -20° to 100° C., preferably 0° C. to room temperature. The reaction is completed within the period of about 30 minutes to 10 hours.

Among the compounds of the general formula (2b) used as starting material for the production of the compounds of this invention, the compound (2c) having the formula where m is 1 can be easily produced according to the process shown in the following reaction formula-6. ##STR6## wherein R⁶ is an alkyl group, and R¹, X and carbon bond at 3- and 4-positions in the carbostyril skeleton are as defined above.

According to this process, a known acyloxycarbostyril derivative represented by the general formula (7) is halogenated and the obtained acyloxy-halogenocarbostyril derivative represented by the general formula (8) is hydrolyzed to produce a hydroxy-halogencarbostyril derivative represented by the general formula (2c). The halogenation reaction conditions are same as described above, and the hydrolysis reaction conditions may be same as described below.

Among the compounds represented by the general formula (4), those compounds which have a halogen atom, a hydroxy group or a phenylalkoxy group at the site of R² are novel compounds, and such compounds can be obtained from the process shown in the following reaction process formula-7. ##STR7## wherein R² ' is a halogen atom, a hydroxy group or a phenylalkoxy group, R⁷ is an organic residue, X is a halogen atom, and R¹, R³, m, l, n and carbon bond at 3- and 4-positions in the carbostyril skeleton are as defined above.

According to this process, a hydroxycarbostyril derivative represented by the general formula (2d) is reacted with an ester derivative represented by the general formula (9) to obtain an ester carbostyril derivative represented by the general formula (4a), and the thus obtained compound of the general formula (4a) is hydrolyzed to produce a corresponding carboxyalkoxycarbostyril derivative represented by the general formula (4b).

The reaction between the compound (2d) and the compound (9) can be accomplished under the ordinary dehydrohalogenation reaction conditions. A variety of basic compounds may be used as the dehydrohalogenating agent in this reaction. Examples of such basic compounds include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metals such as sodium, potassium, etc.; and organic bases such as triethylamine, pyridine, N,N-dimethylaniline, etc. Such reaction can be conducted either in the presence or in the absence of a solvent. A variety of solvents that take no part in the reaction can be used. Recommended examples of such solvents for use in this reaction are alcohols such as methanol, ethanol, propanol, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc.; and ketones such as acetone, methyl ethyl ketone, etc. The ratio of the amounts of compound (2d) to compound (9) is not subject to any specific limitations but can be suitably selected from a wide range. Usually, however, the latter is used in an amount of 1 to 5 times, preferably 1 to 2 times the moles of the former. The reaction temperature may be also suitably selected from a wide range, but usually the reaction is carried out at a temperature between room temperature and 200° C., preferably between 50° and 150° C., for the period of usually about 1 to 10 hours.

The hydrolysis reaction of the compound (4a) is usually conducted in the presence of a catalyst. The catalyst used may be of any type commonly employed for the hydrolysis reactions, and as typical examples of such catalyst, the following may be cited: basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, etc.; and organic acids such as acetic acid, aromatic sulfonic acid, etc. The amount of such catalyst used in the reaction is not defined to any specific extent but may be suitably selected from a wide range. Such hydrolysis reaction can be accomplished in an ordinary way but it proceeds advantageously in a solvent. It is possible to use a variety of solvents which take no part in the reaction, such as for example water, alcohols such as methanol, ethanol, isopropanol, etc.; ketones such as acetone, methyl ethyl ketone, or mixtures thereof. The reaction temperature is not critical and can be suitably selected from a wide range, but usually the reaction is practiced at a temperature between room temperature and 200° C., preferably between 50° and 150° C. The reaction is completed in usually about 5 minutes to 10 hours.

The amines of the general formula (5) used as the starting material in the present invention can be produced easily by various methods such as those expressed by the following reaction processes formulae-8, -9 and -10. ##STR8##

In the above formulae, R⁴ ' is a substituted or unsubstituted phenyl group or phenylalkyl group, R⁴ " is a substituted or unsubstituted cyclohexyl or cyclohexylalkyl group, X is a halogen atom, and R⁴ and R⁵ are as defined above.

According to the reaction process formula-8, the amine represented by the general formula (5) can be easily obtained by subjecting a known amine of the general formula (10) and a known halogen compound of the general formula (11) to a dehydrohalogenation reaction in the presence of a basic compound. According to the reaction process formula-9, the amine represented by the general formula (5) can be produced by subjecting a known amine of the general formula (12) and a known halogen compound of the general formula (13) to a dehydrohalogenation reaction in the presence of a basic compound. These reactions can be simply accomplished similar to a dehydrohalogenation reaction between the compound of the general formula (2) and the compound of the general formula (3).

According to the reaction process formula-10, the cyclohexylamine derivative or cyclohexylalkylamine derivative represented by the general formula (5b) can be easily produced by reducing the benzene nucleus of a known compound of the general formula (5a). Various known nuclear hydrogenation reaction methods may be used for effecting the reduction of the benzene nucleus, but in the present invention, the catalytic reduction method is most advantageous. Such catalytic reduction is carried out in a solvent by using a catalyst according to a commonly employed method. The catalyst used in this reduction reaction may be of the type commonly employed for the nuclear hydrogenation reactions. Examples of such catalyst are platinum catalysts such as platinum black, platinum oxide, colloidal platinum, etc.; palladium catalysts such as palladium black, palladium carbon, colloidal palladium, etc.; rhodium catalysts such as asbestos-filled rhodium, rhodium alumina, etc.; ruthenium catalysts, nickel catalysts such as Raney nickel, nickel oxide, etc.; and cobalt catalysts. The solvent used in this reaction may be, for example, a lower alcohol (such as methanol, ethanol, isopropanol, etc.), water, acetic acid, acetic acid ester, ethylene glycol, an ether (tetrahydrofuran, dioxane, etc.) and a cycloalkane (such as cyclohexane, cyclopentane, etc.). This reaction is carried out under hydrogen pressure (preferably 1 to 100 atm.) at a temperature between room temperature and 100° C. for a period of 1 hour to 2 days.

The haloamides of the general formula (3) used as another starting material in the present invention can be obtained in various ways, for example, by reacting an amine of the general formula (5) and a known halocarboxylic acid of the general formula (14) as shown by the following reaction process formula-11. ##STR9## wherein R³, R⁴, R⁵, l, n and X are all as defined above.

The reaction between the compound (5) and compound (14) can be accomplished in the same way as the above-said amide bond generating reaction. It is also possible in this invention to substitute the compound (14) with a compound having an activated carboxyl group.

Among the compounds of the present invention represented by the general formula (1), the compounds having a hydrogen as to R¹ and also having the double carbon-carbon bonds at 3- and 4-positions in the carbostyril skeleton may be prepared in the form of lactam-lactim type tautomeric compounds ((1e) and (1f)) as shown in the following reaction process formula-12. ##STR10## wherein R², R³, R⁵, m, l and n are as defined above.

Among the compounds represented by the general formula (1), those compounds which have an acidic group can easily form salts with the pharmaceutically acceptable basic compounds. Such basic compounds include the inorganic base compounds, for example metallic hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, etc.; metal carbonates such as sodium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, etc.; alkali metal alcoholates such as sodium methylate, potassium ethylate, etc.; and alkali metals such as sodium, potassium, etc.; and the organic basic compounds such as morpholine, piperazine, piperidine, diethylamine, aniline, etc. Of the compounds represented by the general formula (1), those having a basic group can easily form salts with the usual pharmaceutically acceptable acids which include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.; and organic acids such as acetic acid, p-toluenesulfonic acid, succinic acid, benzoic acid, etc.

The thus obtained compounds of the present invention can be easily isolated and refined by the usual separation means such as precipitation, extraction, recrystallization, column chromatography and preparative thin layer chromatography.

The compounds of the present invention can be administered, either in the form as they are or together with a pharmaceutically acceptable carrier, to animals as well as to human being. No particular restriction is placed on the administration unit forms and the compounds can be used in any desired unit form. Suitable administration unit forms include such oral administration forms as tablets, capsules, granules, etc.; and parenteral administration forms such as injections. The dosage of the active ingredient to be administered is not subject to any particular definition and admits of selection from a wide range, but in order to obtain a desired pharmacological effect, it is recommended to select said dosage from the range of 0.06 to 10 mg per kg body weight per day. It is also suggested to contain 1 to 500 mg of the active ingredient in each unit dose of the administration forms.

The compounds of the present invention can be formed into the desired peroral preparations such as tablets, capsules, solutions, etc., according to a common method. For preparation of tablets, a compound of the present invention is mixed with a pharmaceutically acceptable excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like and shaped into tablets. Capsules can be obtained by mixing a compound of this invention with an inert pharmaceutically acceptable filler or diluent and filling the mixture into rigid gelatin capsules or soft capsules. Sirup or elixir may be prepared by mixing a compound of the present invention with a sweetening such as sucrose, antiseptic such as methyl- and propyl-parabens, colorant, seasoning and/or other suitable additives.

Parenteral preparations can be also obtained according to a common method. In this case, the compound of the present invention is dissolved in a sterilized liquid vehicle. Preferred vehicle is water or saline water. Liquid preparations having desired transparency, stability and parenteral use adaptability can be obtained by dissolving approximately 1 to 500 mg of the active ingredient in a solution of polyethylene glycol which is soluble in both water and organic solvents. Desirably, such liquid preparations contain a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol or the like. Said liquid preparations may also contain a bactericide and fungicide such as benzyl alcohol, phenol or thimerosal and, if necessary, an isotonic agent such as sucrose or sodium chloride, a local anesthetic, stabilizer, buffer, etc. For additional ensurance of stability, the parenteral compositions may be freezed after filling and dehydrated by the known freeze-drying techniques. The freeze-dried powder can be returned to the normal use form just before use.

PREPARATION OF TABLETS

1,000 Tablets for peroral use, each containing 5 mg of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril, are prepared from the following prescription.

    ______________________________________                                         Ingredient             Amount (g)                                              ______________________________________                                         6-[3-(N-Methyl-N-cyclohexylamino-                                              carbonyl)propoxy]carbostyril                                                                          5                                                       Lactose (J.P. = Japanese                                                                              50                                                      Pharmacopoeia)                                                                 Corn starch (J.P.)     25                                                      Crystalline cellulose (J.P.)                                                                          25                                                      Methyl cellulose (J.P.)                                                                               1.5                                                     Magnesium stearate (J.P.)                                                                             1                                                       ______________________________________                                    

The above specified 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, lactose, corn starch and crystalline cellulose are mixed well, and the mixture is added with a 5% aqueous solution of methyl cellulose and then granulated. The obtained granules are passed through a 200 mesh sieve and then dried carefully.

PREPARATION OF TABLETS

1,000 Tablets for peroral use, each containing 5 mg of 6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyril, are preared in the similar way from the following prescription.

    ______________________________________                                         Ingredient           Amount (g)                                                ______________________________________                                         6-{3-[N-Methyl-N-(4-acetoxy-                                                   cyclohexyl)aminocarboxyl]-                                                     propoxy}carbostyril  5                                                         Lactose (J.P.)       50                                                        Corn starch (J.P.)   25                                                        Crystalline cellulose (J.P.)                                                                        25                                                        Methyl cellulose (J.P.)                                                                             1.5                                                       Magnesium stearate (J.P.)                                                                           1                                                         ______________________________________                                    

PREPARATION OF CAPSULES

1,000 Pieces of two-piece rigid gelation capsules for peroral use, each containing 10 mg of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, are prepared from the following prescription.

    ______________________________________                                         Ingredient             Amount (g)                                              ______________________________________                                         6-[3-(N-Methyl-N-cyclohexyl-                                                   aminocarbonyl)propoxy]carbostyril                                                                     10                                                      Lactose (J.P.)         80                                                      Starch (J.P.)          30                                                      Talc (J.P.)            5                                                       Magnesium stearate (J.P.)                                                                             1                                                       ______________________________________                                    

The above components are finely ground, then stirred and mixed sufficiently to form a uniform mixture and then filled into the gelatin capsules with a size convenient for peroral administration.

PREPARATION OF CAPSULES

1,000 Pieces of two-piece rigid gelatin capsules for peroral use, each containing 10 mg of 6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyril, are prepared in the similar way from the following prescription.

    ______________________________________                                         Ingredient           Amount (g)                                                ______________________________________                                         6-{3-[N-Methyl-N-(4-acetoxy-                                                   cyclohexyl)aminocarbonyl]-                                                                          10                                                        propoxy}carbostyril                                                            Lactose (J.P.)       80                                                        Starch (J.P.)        30                                                        Talc (J.P.)          5                                                         Magnesium stearate (J.P.)                                                                           1                                                         ______________________________________                                    

PREPARATION OF INJECTIONS

A sterile aqueous solution suited for parenteral use is prepared from the following prescription.

    ______________________________________                                         Ingredient             Amount (g)                                              ______________________________________                                         6-[3-(N-Methyl-N-cyclohexyl-                                                   aminocarbonyl)propoxy]carbostyril                                                                     1                                                       Polyethylene glycol (J.P.),                                                    [molecular weight: 4,000]                                                                             0.3                                                     Sodium chloride (J.P.) 0.9                                                     Polyoxyethylene sorbitan mono-                                                 oleate (J.P.)          0.4                                                     Sodium metabisulfite   0.1                                                     Methyl-p-hydroxybenzoate (J.P.)                                                                       0.18                                                    Propyl p-hydroxybenzoate (J.P.)                                                                       0.02                                                    Distilled water for injection                                                                         100 ml                                                  ______________________________________                                    

A mixture of the above-prescribed methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sodium metabisulfite and sodium chloride, while stirred, is dissolved in about half the quantity of distilled water at 80° C. The obtained solution is cooled to 40° C., and then 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in that order in said solution. This solution is further added with distilled water for injection to the final regulated volume and then sterilized by sterile filtration with a suitable filter paper.

PREPARATION OF INJECTIONS

A sterile aqueous solution suited for parenteral use is prepared in the way similar to the above from the following prescription.

    ______________________________________                                         Ingredient             Amount (g)                                              ______________________________________                                         6-{3-[N-Methyl-N-(4-acetoxycyclo-                                              hexyl)aminocarbonyl]propoxy}-                                                  carbostyril            1                                                       Polyethylene glycol (J.P.)                                                     [molecular weight: 4,000]                                                                             0.3                                                     Sodium chloride (J.P.) 0.9                                                     Polyoxyethylene sorbitan mono-                                                 oleate (J.P.)          0.4                                                     Sodium metabisulfite   0.1                                                     Methyl p-hydroxybenzoate (J.P.)                                                                       0.18                                                    Propyl p-hydroxybenzoate (J.P.)                                                                       0.02                                                    Distilled water for injection                                                                         100 ml                                                  ______________________________________                                    

The results of the pharmacological tests on the compounds of this invention are shown below.

PHARMACOLOGICAL TEST 1

The platelet aggregation inhibitory effect is measured by using AG-II Aggregometer (manufactured by Bryston Manufacturing Co.). The blood sample used for the test is a 1/9 (by volume) mixture of sodium citrate and whole blood collected from rabbit. Said sample is subjected to 10-minute centrifugal separation at 1,000 r.p.m. to obtain a platelet rich plasma (PRP). The thus obtained PRP is separated, and the remaining blood sample is further subjected to 15-minute centrifugal separation at 3,000 r.p.m. to obtain a platelet poor plasma (PPP).

The number of platelets in the PRP is counted by the Brecher-Clonkite Method, and the PRP is diluted with the PPP to prepare a PRP sample with platelet concentration of 300,000/mm³ for the adenosine diphosphate (ADP)-induced aggregation test. There is also prepared a PRP sample with platelet concentration of 450,000/mm³ for the collagen-induced aggregation test.

0.6 ml of said PRP sample is added into 0.01 ml of a solution of a test compound of a predetermined concentration and the mixture is placed in a 37° C. thermostat for one minute. Then 0.07 ml of an ADP or collagen solution is added to the mixture. Transmittance of this mixture is determined and the change of transmittance is recorded by using the aggregometer at stirrer speed of 1,100 r.p.m. In this test, Auren Beronal buffer (pH 7.35) is used for the preparation of the ADP or collagen solution. ADP is adjusted to a concentration of 7.5×10⁻⁵ M, and the collagen solution is prepared by triturating 100 mg of collagen with 5 ml of said buffer and the supernatant is used as collagen inducer. Adenosine and acetylsalicylic acid are used as controls for the ADP-induced aggregation test and the collagen-induced aggregation test, respectively. The platelet aggregation inhibitory effect is measured in terms of percent inhibition with respect to the aggregation rate of the controls. The aggregation rate is calculated from the following formula:

    Aggregation rate=(c-a)/(b-a)×100

wherein

a: transmittance of PRP

b: transmittance of PRP containing a test compound and an aggregation inducer

c: transmittance of PPP.

The inhibitory effect of the tested compounds on collagen-induced aggregation in rabbit platelets is shown in Table 1, and such effect on ADP-induced aggregation is shown in Table 2. The compounds tested are as follows.

TESTED COMPOUNDS COMPOUNDS OF THE PRESENT INVENTION (NOS. 1-24)

    ______________________________________                                         No.                                                                            ______________________________________                                         1.   6-{3-[N-Methyl-N-(2-methylcyclohexyl)aminocarbonyl]-                           propoxy}carbostyril                                                       2.   6-{3-[N-Methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]-                          propoxy}carbostyril                                                       3.   6-{3-[N-Methyl-N-(4-acetyloxycyclohexyl)amino-                                 carbonyl]propoxy} carbostyril                                             4.   6-{3-[N-Methyl-N-(2-3',4'-dimethoxyphenylethyl)-                               aminocarbonyl]propoxy}carbostyril                                         5.   6-{3-(N-Cyclohexyl-N-benzylaminocarbonyl)propoxy]-                             carbostyril                                                               6.   5-Chloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)-                            propoxy]carbostyril                                                       7.   6-{3-[N-Cyclohexyl-N-(2-chlorocyclohexyl)amino-                                carbonyl]propoxy}-3,4-dihydrocarbostyril                                  8.   6-[2-Hydroxy-3-(N-methyl-N-cyclohexylamino-                                    carbonyl)propoxy]carbostyril                                              9.   6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-2-                                   methylpropoxy]carbostyril                                                 10.  8-Hydroxy-5-[3-(N-Methyl-N-cyclohexylamino-                                    carbonyl)propoxy]-3,4-dihydrocarbostyril                                  11.  6-{3-[N-Benzyl-N-(2-3',4'-dimethoxyphenylethyl)-                               aminocarbonyl]propoxy}-3,4-dihydrocarbostyril                             12.  6,8-Dichloro-5-[3-(N-ethylanilinocarbonyl)-                                    propoxy]-3,4-dihydrocarbostyril                                           13.  6-[3-(N-Cyclohexylaminocarbonyl)propoxy]carbostyril                       14.  6-[3-(N-Allyl-N-cyclohexylaminocarbonyl)propoxy]-                              3,4-dihydrocarbostyril                                                    15.  6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy]-                             3,4-dihydrocarbostyril                                                    16.  6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy]-                             carbostyril                                                               17.  6-[3-(N-Cyclohexylanilinocarbonyl)propoxy]carbostyril                     18.  6-[3-(N,N-Dicyclohexylaminocarbonyl)propoxy]-3,4-                              dihydrocarbostyril                                                        19.  6-[3-(Anilinocarbonyl)propoxy]-3,4-dihydrocarbo-                               styril                                                                    20.  6-[3-(N-Ethylanilinocarbonyl)propoxy]carbostyril                          21.  6-[3-(o,o-Dichloroanilinocarbonyl)propoxy]-3,4-                                dihydrocarbonstyril                                                       22.  6-[4-(N-Butyl-N-cyclohexylaminocarbonyl)-                                      buthoxy]-3,4-dihydrocarbostyril                                           23.  5-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy]  -                           3,4-dihydrocarbostyril                                                    24.  6-[3-(N,N-Diphenylaminocarbonyl)propoxy]-3,4-                                  dihydrocarbostyril                                                        ______________________________________                                    

KNOWN COMPOUNDS (COMPARATIVE COMPOUNDS) (NOS. 25-46)

    ______________________________________                                         No.                                                                            ______________________________________                                         25.  6-(1-Ethoxycarbonylethoxy)-3,4-dihydrocarbostyril                         26.  6-(1-Ethoxycarbonylethoxy)carostyril                                      27.  1-Methyl-6-(1-ethoxycarbonylethoxy)-3,4-dihydro-                               carbostyril                                                               28.  7-(1-ethoxycarbonylethoxy)-3,4-dihydrocarbostyril                         29.  6-(3-Ethoxycarbonylpropoxy)-3,4-dihydrocarbostyril                        30.  6-(1-Amyloxycarbonylethoxy)-3,4-dihydrocarbostyril                        31.  6-(1-Isopropoxycarbonylethoxy)carbostyril                                 32.  5-(3-Ethoxycarbonylpropoxy)-3,4-dihydrocarbostyril                        33.  6-(3-Amyloxycarbonylpropoxy)-3,4-dihydrocarbo-                                 styril                                                                    34.  6-(3-Ethoxycarbonylpropoxy)carbostyril                                    35.  6-(6-Ethoxycarbonylhexyloxy)-3,4-dihydrocarbostyril                       36.  6-(6-Carboxyhexyloxy)-3,4-dihydrocarbostyril                              37.  8-(1-Ethoxycarbonylethoxy)-3,4-dihydrocarbostyril                         38.  6-(1-Methyl-1-carboxyethoxy)-3,4-dihydrocarbostyril                       39.  6-(3-Carboxypropoxy)carbostyril                                           40.  6-(3-Cyclohexyloxycarbonylpropoxy)-3,4-dihydro-                                carbostyril                                                               41.  5-(N-Isopropylaminocarbonylethoxy)-3,4-dihydro-                                carbostyril                                                               42.  5-(Morpholinocarbonylmethoxy)-3,4-dihydro-                                     carbostyril                                                               43.  5-(N,N-dimethylaminocarbonylmethoxy)-3,4-dihydro-                              carbostyril                                                               44.  1-Ethyl-5-[3-(N-benzylaminocarbonyl)propoxy]-                                  3,4-dihydrocarbostyril                                                    45.  6-[3-(N-Propylaminocarbonyl)-2-methylpropoxy]-                                 3,4-dihydrocarbostyril                                                    46.  Aspirin                                                                   ______________________________________                                    

                  TABLE 1                                                          ______________________________________                                         Inhibition effect of carbostyril derivatives                                   on collagen induced aggregation in rabbit                                      platelet                                                                                      Concentration of the test                                              Test    compound solution                                                      compound                                                                               10.sup.-4                                                                               10.sup.-5                                                                              10.sup.-6                                                                             10.sup.-7                                      No.     mole     mole    mole   mole                                    ______________________________________                                         Compounds                                                                               1         --%      100.0%                                                                               100.0% 21.1%                                 of the   2         --       100.0 89.7   --                                    present  3         90.8     84.8  61.9   --                                    invention                                                                               4         82.9     46.5  19.2   --                                             5         --       91.8  88.4   30.6                                           6         100.0    53.3  12.3   --                                             7         91.5     89.9  50.3   --                                             8         85.5     86.8  2.9    --                                             9         100.0    100.0 100.0  11.2                                           10        91.8     29.3  --     --                                             11        88.1     75.8  28.1   --                                             12        82.6     65.2  33.8   --                                             13        87.5     45.8  23.3   --                                             14        82.4     42.3  15.7   --                                             15        94.0     92.6  34.1   --                                             16        --       90.5  90.2   57.0                                           17        91.5     53.8  16.7   --                                             18        87.5     59.4  50.0   --                                             19        93.8     17.4  --     --                                             20        91.3     76.3  43.2   --                                             21        95.1     27.6  --     --                                             22        85.6     78.5  28.7   --                                             23        76.5     58.7  13.5   --                                             24        82.7     43.5  15.5   --                                    ______________________________________                                         Known    25        71       20    2      --                                    compounds                                                                               26        67       12    -6     --                                    (Reference                                                                              27        36       --    0      --                                    compounds)                                                                              28        2        --    8      --                                             29        92       38    8      --                                             30        88       8     0      --                                             31        55       25    3      --                                             32        90       8     5      --                                             33        48       22    6      --                                             34        100      86    18     --                                             35        31       13    6      --                                             36        15       14    2      --                                             37        5        --    2      --                                             38        5        3     0      --                                             39        28       15    0      --                                             40        12       8     0      --                                             41        17       --    0      --                                             42        5        0     0      --                                             43        27       13    0      --                                             44        7        0     0      --                                             45        12       5     0      --                                             46        65       9     7      --                                    ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                                Inhibition effect of carbostyril derivatives                                   on ADP-induced aggregation in rabbit                                           platelet                                                                               Concentration of the test                                              Test    compound solution                                                      compound                                                                               10.sup.-4                                                                               10.sup.-5                                                                              10.sup.-6                                                                            10.sup.-7                                       No.     mole     mole    mole  mole                                     ______________________________________                                         Compounds                                                                               1         100.0%   73.0% 42.4% 4.3%                                   of the   2         --       90.3  54.3  --                                     present  3         91.5     75.0  20.8  --                                     invention                                                                               4         70.4     16.1  6.9   --                                              5         --       90.7  61.2  18.9                                            6         87.2     5.4   --    --                                              7         89.8     82.9  38.4  --                                              8         91.7     41.1  --    --                                              9         92.8     70.4  5.8   --                                              10        53.9     18.4  --    --                                              11        87.5     12.5  16.9  --                                              12        71.7     33.8  12.7  --                                              13        39.6     24.8  18.0  --                                              14        41.3     25.7  15.1  --                                              15        88.3     26.8  10.8  --                                              16        --       91.7  62.1  32.8                                            17        82.5     38.7  12.3  --                                              18        86.4     37.5  12.6  --                                              19        24.6     16.2  --    --                                              20        82.5     31.7  13.5  --                                              21        36.8     5.3   --    --                                              22        71.5     32.7  10.5  --                                              23        73.6     26.1  8.7   --                                              24        43.2     22.3  13.4  --                                     Known    25        57       25    5     --                                     compounds                                                                               26        86       54    -6    --                                     (Reference                                                                              27        36       --    0     --                                     compounds)                                                                              28        -18      --    14    --                                              29        100      97    10    --                                              30        100      79    20    --                                              31        74       38    7     --                                              32        65       18    2     --                                              33        82       58    0     --                                              34        100      90    25    --                                              35        37       15    10    --                                              36        13       8     7     --                                              37        3        --    11    --                                              38        10       5     3     --                                              39        52       23    5     --                                              40        28       16    7     --                                              41        18       13    7     --                                              42        13       6     0     --                                              43        22       17    8     --                                              44        14       6     0     --                                              45        32       17    9     --                                              46        7        0     --    --                                     ______________________________________                                    

PHARMACOLOGICAL TEST 2

A water suspension of test compound was administered at the dose of 30 mg/kg to the overnight fasted male Wister rats and male beagle dogs, and after a predetermined period of time, blood was collected from said animals to obtain plasma. 2 to 3 Milliliters of 0.1 N-NaOH and 2 ml of CHCl₃ were added to 1 ml of the obtained plasma, and the mixture was shaken and extracted in a shaker for 2 hours, and after centrifugal separation, the organic layer was washed with 2 ml of 0.1 N-HCl. This organic layer was then subjected to a freezing and thawing treatment, and after evaporating chloroform under nitrogen stream, the residue was redissolved in 100 μl of chloroform and spotted on a thin layer plate of "Silica Gel 60 F₂₅₄ " manufactured by Merck & Co., Inc. This was developed in a chloroform: butanol mixed solvent (5:1) and determined by measuring the spots with same Rf value as the test compound according to the absorbance method by using Shimazu CS-910 Thin Layer Chromato-scanner, and therefrom the concentration (μg/ml) of test compound A in blood was determined. The results are shown in Table 3.

                  TABLE 3                                                          ______________________________________                                         Test                                                                           com-                                                                           pound     Test    Concentration in blood (μg/ml)                            No.       animal  1 hr.  2 hr.                                                                               4 hr.                                                                               6 hr.                                                                               8 hr.                                                                               12 hr.                            ______________________________________                                         Com-          Rat     1.05 1.62 0.94 0.53 --   0.48                            pounds                                                                               1                                                                        of the        Beagle  0.28 0.31 0.21 0.13 0.08 0.05                            present       dog                                                              in-           Rat     0.90 0.74 1.10 0.28 --   0.64                            vention       Rat     1.06 3.80 0.71 0.32 --   0.73                                  16      Rat     0.88 0.88 0.83 0.02 --   0.78                                          Beagle                                                                         dog     0.23 0.28 0.14 0.11 0.05 0.04                                          Beagle                                                                         dog     0.13 0.31 0.33 0.21 0.15 0.07                                  18      Rat     1.32 1.74 1.02 0.69 0.56 0.42                                          Beagle                                                                         dog     0.36 0.23 0.32 0.17 0.13 0.06                                  20      Rat     0.95 1.37 0.92 0.46 --   0.28                                          Beagle                                                                         dog     0.32 --   --   0.08 0.05 --                                    23      Rat     1.53 2.24 0.94 0.54 0.39 0.52                                          Beagle                                                                         dog     0.43 0.29 0.21 0.14 0.05 0.07                            Known         Rat     0.01 0    0    --   --   --                              com-  29                                                                       pounds        Beagle                                                                         dog     0.01 0    0    --   --   --                                            Rat     0.01 0    0    --   --   --                                    34      Beagle                                                                         dog     0    0    --   --   --   --                              ______________________________________                                    

PHARMACOLOGICAL TEST 3

The obstructive action against cyclic AMP phosphodiesterase was measured according to the activity measuring method described in "Biochimica et Biophysica Acta", Vol. 429, pp. 485-497 (1976) and "Biochemical Medicine", Vol. 10, pp. 301-311 (1974).

That is, for determining the obstructive activity against cyclic AMP phosphodiesterase, 10 ml of a solution obtained by adding 1 mmol of MgCl₂ into 50 mmol of tris-hydrochloric acid buffer with pH 7.4 was added to the platelets obtained by further centrifuging the abovesaid rabbit PRP at 3,000 r.p.m. for 10 minutes, and the suspended platelets were ground by a Teflon potter type homogenizer. This was followed by two times of freezing and thawing treatment and 300-second fracturing with 200 watt supersonic waves. After additional 60-minute centrifugation with 100,000 xg, the supernatant was collected to use it as a crude enzyme solution.

10 Milliliters of this crude buffer solution was added to a 1.5×20 cm DEAE-cellulose column which has previously been buffered with 50 mmol of tris-acetate buffer (pH 6.0), followed by washing and elution with 30 ml of 50 mmol tris-acetate buffer, and this buffer solution was subjected to linear gradient elution with 0 to 0.5 moles of sodium acetate-tris-acetate buffer. The flow rate was 0.5 ml/min, and 5 ml of each fraction was batched out. This operation gave a fraction which has low activity of less than 2 n mole/ml/min with high (100 μmole) cyclic AMP substrate concentration and still has high activity of over 100 p mole/ml/min with low (0.4 μmole) cyclic AMP substrate concentration. This fraction was used as cyclic AMP phosphodiesterase.

0.1 Milliliter of an aqueous solution of each test compound of a specified concentration was mixed with 40 mmol of tris-hydrochloric acid buffer (pH 8.0, containing 50 μg of cow serum albumin and 4 mmol of MgCl₂) containing predetermined 1.0 μmol of cyclic AMP (tritium cyclic AMP), and 0.2 ml of this mixed solution was used as substrate solution.

0.2 Milliliter of the above-prepared cyclic AMP phosphodiesterase of a predetermined concentration was added to said substrate solution and the mixture was reaction at 30° C. for 20 minutes, producing tritium 5'-AMP from the tritium cyclic AMP.

The reaction system was then immersed in boiling water for 2 minutes to stop the reaction, and then this reaction solution was cooled in ice water and, for converting the produced tritium 5'-AMP into tritium adenosine, the solution was added with 0.05 ml (1 mg/ml) of snake poison as 5'-nucleotidase and reacted at 30° C. for 10 minutes. The whole amount of this reaction solution was then added to a cation exchange resin (AG 500 W×4, 200-400 meshes, manufactured by Bio-Rad Co., column size: 0.5×1.5 cm), and the produced tritium anodesine alone was allowed to combine, washed with 6 ml of distilled water and eluted with 1.5 ml of 3 N-ammonia water. The whole quantity of the elutant was added with 10 ml of a triton-toluene type scintillator and the produced tritium adenosine was measured by a liquid scintillation counter to determine the phosphodiesterase activity.

In this way, the phosphodiesterase activation value (Vs) of the test compounds of the respective concentrations was determined, and the phosphodiesterase obstruction rate (%) was determined from said activation value (Vs) and control value (Vc) (obtained from water not containing any test compound) from the following formula: ##EQU1## Known papaverine and 1-methyl-3-isobutylxanthine were used as controls. The results are shown in Table 4.

                  TABLE 4                                                          ______________________________________                                         Test     Concentration of test compound solution                               compound 10.sup.-4                                                                              10.sup.-5                                                                              10.sup.-6                                                                            10.sup.-7                                                                            10.sup.-8                                                                            10.sup.-9                           No.      mole    mole    mole  mole  mole  mole                                ______________________________________                                          3       --      98.5    95.5  88.4  61.1  13.4                                16       --      80.5    87.5  79.3  22.3   7.1                                Papaverine                                                                              100     99.8    91.4  57.3  --    --                                  1-Methyl-3-                                                                    isobutyl-                                                                               98.5    85.7    67.4   3.2  --    --                                  xanthine                                                                       ______________________________________                                    

ACUTE TOXICITY TEST

The test compounds were administered orally to the mice and LD₅₀ (mg/kg) of the compounds was determined. The results are shown in Table 5 below.

                  TABLE 5                                                          ______________________________________                                                               LD.sub.50 (mg)                                                                 Male mice                                                         Test         Oral                                                              compound     administration                                           ______________________________________                                         Compounds  1              >1000                                                of the     2              >1000                                                present    3              >1000                                                invention  4              >1000                                                           5              >1000                                                           6              >1000                                                           7              >1000                                                           8              >1000                                                           9              >1000                                                           10             >1000                                                           11             >1000                                                           12             >1000                                                           13             >1000                                                           14             >1000                                                           15             >1000                                                           16             >1000                                                           17             >1000                                                           18             >1000                                                           19             >1000                                                           20             >1000                                                           21             >1000                                                           22             >1000                                                           23             >1000                                                           24             >1000                                                Known      25             >1000                                                compounds  26             >1000                                                           27             800 ˜ 1000                                                28             >1000                                                           29             >1000                                                           30             >1000                                                           31             900 ˜ 1000                                                32             >1000                                                           33             >1000                                                           34             >1000                                                           35             750 ˜ 1000                                                36             >1000                                                           37             900 ˜ 1000                                                38             800 ˜ 1000                                                39             >1000                                                           40             500 ˜ 800                                                 41             500 ˜ 800                                                 42             400 ˜ 600                                                 43             500 ˜ 700                                                 44             500 ˜ 600                                                 45             500 ˜ 800                                      ______________________________________                                    

CONSIDERATION ON PHARMACOLOGICAL DATA

(1) The results of Tables 1 to 3 indicate that the platelet aggregation inhibitory effect of the compounds of this invention is equal to or higher than that of the known carboxy or esterocarbostyril derivatives and yet the compounds of this invention are far longer in said effect retention time than the known derivatives.

It is also noted that the compounds of this invention are far higher in platelet aggregation inhibitory effect than the known amidocarbostyril derivatives and aspirin.

(2) The results of Table 4 indicate that the compounds of this invention are far stronger in phosphodiesterase obstructing action than known 1-methyl-3-isobutylxanthine and equal to or higher than papaverine and also selectively obstruct cyclic AMP phosphodiesterase.

Shown in the following are some reference examples for production of the compounds which are used as starting material in the preparation of the compounds of this invention.

REFERENCE EXAMPLE 1

24 Grams of 5-hydroxy-3,4-dihydrocarbostyril is suspended in 200 ml of acetic acid and 300 ml of chloroform. This suspension is adjusted to 40° to 50° C., and then 36 ml of sulfuryl chloride is added dropwise thereto under agitation, followed by one-hour agitation at the same temperature. The reaction solution is poured into ice-water and the precipitate is filtered out. This product is recrystallized from methanol to obtain 20 gr of 5-hydroxy-6,8-dichloro-3,4-dihydrocarbostyril in the form of colorless plate-like crystals with melting point of 246°-248° C.

REFERENCE EXAMPLE 2

20 Grams of 6-hydroxy-3,4-dihydrocarbostyril is suspended in 100 ml of acetic acid and 200 ml of chloroform, and after adjusting this suspension to 40° to 50° C., 28 ml of sulfuryl chloride is added dropwise to said suspension under agitation, followed by one-hour agitation at the same temperature. The reaction solution is poured into ice-water and the precipitate is filtered out and recrystallized from methanol, resultantly obtaining 3.5 g of 6-hydroxy-5,7,8-trichloro-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 251° C. (decomposed).

REFERENCE EXAMPLE 3

24 Grams of 8-hydroxy-3,4-dihydrocarbostyril is dissolved in 200 ml of acetic acid and 200 ml of chloroform, and after adjusting the temperature of this solution to 40° to 50° C., 36 ml of sulfuryl chloride is added dropwise to said solution under agitation and the mixture is further agitated for one hour at the same temperature. The reaction solution is poured into ice-water and the precipitate is filtered out and recrystallized from methanol, producing 25 g of 8-hydroxy-5,6,7-trichloro-3,4-dihydrocarbostyril in the form of white powdery crystals. Melting point: 267°-269° C. (decomposed).

REFERENCE EXAMPLES 4-5

The following compounds are obtained in the same way as above-shown Reference Examples 1-3.

    ______________________________________                                         Reference                           Melting                                    Example                  Crystal    point                                      No.     Compound         form       (°C.)                               ______________________________________                                         4       5-Hydroxy-8-bromo-3,4-                                                                          Colorless  212-                                               dihydrocarbostyril                                                                              needle-like                                                                               213.5                                                               crystals   (decom-                                                                        posed)                                     5       6-Hydroxy-5-chlorocarbo-                                                                        Colorless  307.5-                                             styril           crystals   308.5                                      ______________________________________                                    

REFERENCE EXAMPLE 6

To a solution of 4.5 g of 5-hydroxy-8-bromo-3,4-dihydrocarbostyril in 100 ml of ethanol is added 3.8 g of ethyl bromoacetate and 3.8 g of potassium carbonate, and the mixture is agitated under reflux for 4 hours. The reaction solution is poured into ice-water and the precipitate is filtered out and recrystallized from methanol, obtaining 3.8 g of colorless needle-crystals of 5-ethoxycarbonylmethoxy-8-bromo-3,4-dihydrocarbostyril. m.p., 215°-216° C.

REFERENCE EXAMPLES 7-13

The following compounds are obtained by following the process of above-said Reference Example 6.

    ______________________________________                                         Reference                                                                      Example                                                                        No.                                                                            ______________________________________                                         7       5-(3-Ethoxycarbonylpropoxy)-                                                                       Colorless                                                                               161-                                              8-bromo-3,4-dihydro-                                                                               flake-like                                                                              161.5                                             carbostyril         crystals                                           8       5-(3-Ethoxycarbonylpropoxy)-                                                                       Colorless                                                                               171.5-                                            8-iodo-3,4-dihydro- needle-  172                                               carbostyril         like                                                                           crystals                                           9       5-(3-Ethoxycarbonylpropoxy)-                                                                       Colorless                                                                               164-                                              6,8-diiodo-3,4-dihydro-                                                                            needle-  164.5                                             carbostyril         like                                                                           crystals                                           10      5-(3-Ethoxycarbonylpropoxy)-                                                                       Colorless                                                                               146-                                              6,8-dichloro-3,4-dihydro-                                                                          needle-  147.5                                             carbostyril         like                                                                           crystals                                           11      5-Chloro-6-ethoxycarbonyl-                                                                         Colorless                                                                               247-                                              methoxycarbostyril  needle-  248                                                                   like                                                                           crystals                                           12      5-Chloro-6-(3-methoxy-                                                                             Colorless                                                                               208.5-                                            carbonylpropoxy)carbostyril                                                                        flake-   209                                                                   like                                                                           crystals                                           13      8-(3-Ethoxycarbonylpropoxy)-                                                                       Colorless                                                                               142-                                              5,6,7-trichloro-3,4-dihydro-                                                                       needle-  143                                               carbostyril         like                                                                           crystals                                           ______________________________________                                    

REFERENCE EXAMPLE 14

3.6 Grams of 5-ethoxycarbonylmethoxy-8-bromo-3,4-dihydrocarbostyril is dissolved in 150 ml of ethanol, and to this solution is added a 50 ml water solution of 5 g of potassium hydroxide, and the mixture is refluxed for 5 hours. The solvent is distilled off and the residue is dissolved in water and then made acidic with hydrochloric acid. The precipitate is filtered out and recrystallized from aqueous ethanol to obtain 2.5 g of 5-carboxymethoxy-8-bromo-3,4-dihydrocarbostyril in the form of colorless needle-like crystals, m.p., 255°-256° C. (decomposed).

REFERENCE EXAMPLES 15-21

The following compounds are obtained by the method similar to Reference Example 14.

    ______________________________________                                         Reference                                                                      Example                                                                        No.                                                                            ______________________________________                                         15      5-(3-Carboxypropoxy)-8-                                                                         Colorless                                                                               226-                                                 bromo-3,4-dihydrocarbo-                                                                         crystals 227.5                                                styril                                                                 16      5-(3-Carboxypropoxy)-8-                                                                         Colorless                                                                               233-                                                 iodo-3,4-dihydro-                                                                               crystals 234                                                  carbostyril               (decomposed)                                 17      5-(3-Carboxypropoxy)-6,8-                                                                       Colorless                                                                               202.5-                                               diiodo-3,4-dihydro-                                                                             crystals 203.5                                                carbostyril               (decomposed)                                 18      5-(3-Carboxypropoxy)-6,8-                                                                       Colorless                                                                               203.5-                                               dichloro-3,4-dihydro-                                                                           crystals 204.5                                                carbostyril                                                            19      6-Carboxymethoxy-5-                                                                             Colorless                                                                               320 or higher                                        chlorocarbostyril                                                                               needle-                                                                        like                                                                           crystals                                              20      6-(3-Carboxypropoxy)-                                                                           Colorless                                                                               251-                                                 5-chlorocarbostyril                                                                             needle-  253                                                                   like                                                                           crystals                                              21      8-(3-Carboxypropoxy)-                                                                           Colorless                                                                               203-                                                 5,6,7-trichloro-3,4-                                                                            crystals 205                                                  dihydrocarbostyril                                                     ______________________________________                                    

REFERENCE EXAMPLE 22

17 Grams of p-methylaminophenol, 20 ml of triethylamine and 9 g of 5% rhodium alumina are added to 200 ml of methanol and the mixture is shaken at the temperature of 60° to 70° C. and under hydrogen pressure of 3 to 4 atm. for 16 hours to effect hydrogenation. After the reaction, the catalyst is filtered off and the mother liquor is concentrated and evaporated to dryness, and the residue is added with 500 ml of chloroform and 200 ml of 5% aqueous NaOH solution. After separating the liquid, the chloroform layer is washed with water and concentrated, and the residue is further distilled under reduced pressure. This treatment gives 11 g of 4-methylaminocyclohexanol with boiling point of 123°-129° C. (at 22 mmHg).

REFERENCE EXAMPLE 23

19 Grams of 2-aminocyclohexanol, 20 g of isopropyl iodide and 15 g of potassium carbonate are added to 50 ml of dimethylformamide and the mixture is agitated at 80°-90° C. for 20 hours. After the reaction, the solution is concentrated and the residue is dissolved in chloroform, washed with water and then dried with anhydrous sodium sulfate (Na₂ SO₄). After filtering off the desiccant, the mother liquor is concentrated and the residue is crystallized with petroleum ether. The obtained crystals are recrystallized from ethanol, resultantly obtaining 8 g of 2-isopropylaminocyclohexanol in the form of colorless crystals. m.p. 54°-55° C.

REFERENCE EXAMPLE 24

26 Milliliters of N-methylcyclohexylamine is added to 400 ml of ethyl acetate, and then 25 ml of 4-chlorobutyryl chloride and 33.5 ml of triethylamine are added dropwise simultaneously to said solution under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. This dropwise addition is performed by spending 20 minutes, followed by 1-hour agitation at room temperature. After the reaction, the reaction solution is added with water, and after separating the liquid, the organic layer is washed with a saturated potassium carbonate solution (K₂ CO₃ water), 10% hydrochloric acid and water in that order and then dried with anhydrous Na₂ SO₄. Sodium sulfate is filtered off and the mother liquor is concentrated and then distilled under reduced pressure to obtain 41.5 g of colorless liquid of N-(4-chlorobutyryl)-N-methylcyclohexylamine with boiling point of 133°-136° C. (2 mmHg).

Now the process for producing the compounds of this invention is described by way of examples.

EXAMPLE 1

2.5 Grams of 5-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 2.0 ml of N-methylmorpholine are added to 200 ml of methylene chloride, and then 1.0 ml of methyl chloroformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After this dropwise addition, the mixture is further agitated at room temperature for 30 minutes and then added with 1.3 ml of N-ethylaniline, followed by additional 4-hour agitation at the same temperature. After the reaction, the reaction solution is added with water, and after liquid separation, the organic layer is washed with a dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na₂ SO₄. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ethanol, consequently obtaining 2.6 g of 5-[3-(N-ethylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 179.5°-180.5° C.

EXAMPLE 2

2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.8 ml of pyridine are added to 50 ml of tetrahydrofuran, and then 1.0 ml of methyl bromoformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 5°-15° C. after addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.2 g of N-methylcyclohexylamine, followed by additional 3-hour agitation. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from chloroform-ethanol to obtain 2.3 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with m.p. of 184.5°-186° C.

EXAMPLE 3

2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.4 g of potassium carbonate are added to 50 ml of dimethylformamide, and then 1.1 ml of isobutyl chloroformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After said dropwise addition, the mixture is further agitated at 30°-40° C. for 1.5 hours and then added with 1.4 g of N-allylcyclohexylamine, followed by additional 2-hour agitation at the same temperature. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water, and the obtained crude crystals are recrystallized from ethyl acetate petroleum ether, whereby there is obtained 2.7 g of colorless needle-like crystals of 6-[3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril with melting point of 105°-107° C.

EXAMPLE 4

2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 200 ml of ethyl acetate, and then 1.0 ml of ethyl chloroformate is added dropwise to this solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.1 ml of N-methylaniline, followed by additional 2-hour agitation. The reaction solution is added with water, and after liquid separation, the organic layer is washed with a dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na₂ SO₄. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from chloroform-petroleum ether to obtain 2.2 g of 6-[3-(N-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needlelike crystals, m.p. 129.5°-131.5° C.

EXAMPLES 5-68

The compounds shown in Table 6 below are obtained according to the similar process to Examples 1-4.

                                      TABLE 6                                      __________________________________________________________________________      ##STR11##                                                                          Position of                                                                    the sub-                                                                             Bonding                            Melting                          Example                                                                             stituted                                                                             at 3- and                    Crystal                                                                              point                            No.  side chain                                                                           4-positions                                                                          n' R.sup.4    R.sup.5  form  (°C.)                     __________________________________________________________________________     5    5     Single bond                                                                          3                                                                                  ##STR12## CH.sub.3 Colorless rhombic crystals                                                           133-134                          6    5     Single bond                                                                          3                                                                                  ##STR13## CH.sub.2 CHCH.sub.2                                                                     Colorless needle-like crystals                                                       116.5-118                        7    5     Single bond                                                                          3                                                                                  ##STR14## H        Colorless needle-like crystals                                                       211-212.5                        8    5     Double bond                                                                          3                                                                                  ##STR15## CH.sub.3 Colorless needle-like                                                                172.5-174                        9    5     Double bond                                                                          3                                                                                  ##STR16## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       216.5-218.5                      10   5     Single bond                                                                          4                                                                                  ##STR17## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like crystals                                                       121-123.5                        11   6     Single bond                                                                          1                                                                                  ##STR18## C.sub.2 H.sub.5                                                                         Colorless rhombic crystals                                                           133-135                          12   6     Single bond                                                                          1                                                                                  ##STR19## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless rhombic crystals                                                           111-113                          13   6     Single bond                                                                          1                                                                                  ##STR20## H        Colorless needle-like crystals                                                       197-198                          14   6     Single bond                                                                          1                                                                                  ##STR21## H        Colorless needle-like crystals                                                       191.5-192.5                      15   6     Single bond                                                                          3                                                                                  ##STR22## H        Colorless needle-like crystals                                                       220-221                          16   6     Single bond                                                                          3                                                                                  ##STR23## CH.sub.3 Colorless needle-like crystals                                                       144-146                          17   6     Single bond                                                                          3                                                                                  ##STR24##                                                                                 ##STR25##                                                                              Colorless needle-like crystals                                                       182-184                          18   6     Single bond                                                                          3                                                                                  ##STR26## H        Colorless plate-like crystals                                                        186-187                          19   6     Single bond                                                                          3                                                                                  ##STR27## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless rhombic crystals                                                           108-110                          20   6     Single bond                                                                          3                                                                                  ##STR28##                                                                                 ##STR29##                                                                              Colorless needle-like crystals                                                       201-205                          21   6     Single bond                                                                          3                                                                                  ##STR30## H        Colorless needle-like crystals                                                       186-187.5                        22   6     Single bond                                                                          3                                                                                  ##STR31## H        Colorless needle-like crystals                                                       265-266 (decomposed)             23   6     Single bond                                                                          3                                                                                  ##STR32## H        Colorless rhombic crystals                                                           214-215 (decomposed)             24   6     Single bond                                                                          4                                                                                  ##STR33## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like  crystals                                                      109.5-111.5                      25   6     Single bond                                                                          4                                                                                  ##STR34## CH.sub.3 Colorless rhombic crystals                                                           129.5-131                        26   6     Single bond                                                                          4                                                                                  ##STR35## H        Colorless needle-like crystals                                                       183-184.5                        27   6     Double bond                                                                          3                                                                                  ##STR36## H        Colorless needle-like crystals                                                       251-252                          28   6     Double bond                                                                          3                                                                                  ##STR37## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       167.5-169                        29   6     Double bond                                                                          3                                                                                  ##STR38##                                                                                 ##STR39##                                                                              Colorless needle-like crystals                                                       174-175                          30   6     Double bond                                                                          3                                                                                  ##STR40## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like crystals                                                       159-160                          31   6     Double bond                                                                          3                                                                                  ##STR41##                                                                                 ##STR42##                                                                              Colorless needle-like crystals                                                       228.5-230.5                      32   6     Double bond                                                                          3                                                                                  ##STR43##                                                                                 ##STR44##                                                                              Colorless needle-like crystals                                                       180-181.5                        33   6     Double bond                                                                          3                                                                                  ##STR45## H        Colorless needle-like crystals                                                       251.5-253                        34   6     Double bond                                                                          3                                                                                  ##STR46## CH.sub.3 Colorless needle-like crystals                                                       187-189                          35   6     Double bond                                                                          3                                                                                  ##STR47## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       115.5-117                        36   6     Double bond                                                                          3                                                                                  ##STR48## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like crystals                                                       159-160.5                        37   6     Double bond                                                                          3                                                                                  ##STR49## CH.sub.3 Colorless needle-like crystals                                                       143-143.5                        38   6     Double bond                                                                          3                                                                                  ##STR50## H        Colorless needle-like crystals                                                       222.5-224                        39   6     Double bond                                                                          3                                                                                  ##STR51## H        Colorless needle-like crystals                                                       236-237                          40   6     Double  bond                                                                         4                                                                                  ##STR52## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like crystals                                                       151-153.5                        41   5     Single bond                                                                          3                                                                                  ##STR53## H        Colorless needle-like crystals                                                       241.5-242                        42   5     Single bond                                                                          3                                                                                  ##STR54## H        Colorless needle-like crystals                                                       206-207                          43   5     Single bond                                                                          6                                                                                  ##STR55## C.sub.2 H.sub.5                                                                         Colorless plate-like crystals                                                        129-131.5                        44   5     Double bond                                                                          3                                                                                  ##STR56## CH.sub.3 Colorless flake-like crystals                                                        223-225 (decomposed)             45   5     Double bond                                                                          3                                                                                  ##STR57## H        Colorless plate-like crystals                                                        171-175                          46   5     Double bond                                                                          3                                                                                  ##STR58## H        Colorless needle-like crystals                                                       241-242 (decomposed)             47   6     Single bond                                                                          1                                                                                  ##STR59## H        Colorless needle-like crystals                                                       202.5-204                        48   6     Double bond                                                                          1                                                                                  ##STR60## CH.sub.3 Pale- yellowish needle-like                                                    crystals                                                                             131-133.5                        49   6     Single bond                                                                          3                                                                                  ##STR61## CH.sub.3 Colorless needle-like crystals                                                       108-112                          50   6     Single bond                                                                          3                                                                                  ##STR62## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       110-111.5                        51   6     Double bond                                                                          3                                                                                  ##STR63## H        Colorless needle-like crystals                                                       209-210                          52   6     Double bond                                                                          3                                                                                  ##STR64## CH.sub.2 CH.sub.2 CH.sub.3                                                              Colorless needle-like crystals                                                       182-184.5                        53   6     Double bond                                                                          4                                                                                  ##STR65## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like crystals                                                       151-153.5                        54   6     Single bond                                                                          6                                                                                  ##STR66## C.sub.2 H.sub.5                                                                         Colorless  needle-like crystals                                                      111-112.5                        55   6     Single bond                                                                          6                                                                                  ##STR67## CH.sub.2 CH.sub.2 CH.sub.3                                                              Colorless needle-like crystals                                                       90.5-92                          56   7     Single bond                                                                          3                                                                                  ##STR68## CH.sub.3 Colorless rhombic crystals                                                           114.5-117                        57   8     Double bond                                                                          1                                                                                  ##STR69## H        Colorless needle-like crystals                                                       235-236                          58   8     Double bond                                                                          1                                                                                  ##STR70## CH.sub.3 Colorless  rhombic crystals                                                          176-178                          59   8     Single bond                                                                          3                                                                                  ##STR71## CH.sub.3 Colorless rhombic crystals                                                           141-142                          60   8     Single bond                                                                          3                                                                                  ##STR72## H        Colorless rhombic crystals                                                           193-195.5                        61   6     Double bond                                                                          3                                                                                  ##STR73## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       150-152                          62   6     Double bond                                                                          3                                                                                  ##STR74##  C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       158-160                          63   6     Double bond                                                                          3                                                                                  ##STR75## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       145-147                          64   6     Double bond                                                                          3                                                                                  ##STR76## C.sub.2 H.sub.5                                                                         Colorless needle-like crystals                                                       143-144.5                        65   6     Double bond                                                                          3                                                                                  ##STR77## (CH.sub.2).sub.4 CH.sub.3                                                               Colorless needle-like crystals                                                       156.5-157.5                      66   6     Double bond                                                                          3                                                                                  ##STR78## (CH.sub.2).sub.5 CH.sub.3                                                               Colorless needle-like crystals                                                       129-132                          67   6     Double bond                                                                          3                                                                                  ##STR79## (CH.sub.2).sub.7 CH.sub.3                                                               Colorless crystals                                                                   100-103                          68   6     Single bond                                                                          3                                                                                  ##STR80## (CH.sub.2).sub.3 CH.sub.3                                                               Colorless rhombic crystals                                                           142-143.5                        __________________________________________________________________________

EXAMPLE 69

2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 150 ml of dimethylformamide, and the mixture is further added dropwise with 1.3 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added with 1.3 ml of cyclohexylmethylamine and further agitated for 1 hour. After the reaction, the reaction solution is poured into about 1 liter of water and the precipitated crystals are filtered out and washed with water. The obtained crystals are dried and recrystallized from chloroform-petroleum ether to obtain 3.0 g of 6-{3-[N-(cyclohexylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with m.p. of 170°-172° C.

EXAMPLES 70-72

The compounds shown in Table 7 are obtained according to the similar process of Example 69.

                  TABLE 7                                                          ______________________________________                                          ##STR81##                                                                          Bonding                            Melting                                Ex.  at 3,4-                    Crystal point                                  No.  positions                                                                               n'    R.sup.4     form    (°C.)                           ______________________________________                                         70   Single bond                                                                             1                                                                                     ##STR82##  Colorless needle-like crystals                                                         174.5- 176                             71   Single bond                                                                             3                                                                                     ##STR83##  Colorless needle-like crystals                                                         138- 139.5                             72   Double bond                                                                             3                                                                                     ##STR84##  Colorless needle-like crystals                                                         173- 175                               ______________________________________                                    

EXAMPLE 73

1.3 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 0.8 ml of triethylamine are added to 50 ml of DMF, and the mixture is added dropwise with 0.65 ml of isobutyl chloroformate under external ice cooling and agitation at internal temperature of 0° to 10° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added dropwise with 0.7 g of N-ethylcyclohexylamine and further agitated at room temperature for 2 hours. The solvent is distilled off and the residue is dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid, aqueous K₂ CO₃ solution and water in that order and then dried with anhydrous Na₂ SO₄. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene to obtain 0.8 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 114°-115.5° C.

EXAMPLE 74

1.3 Grams of 6-(3-carboxy-2-methylpropoxy)-carbostyril and 0.8 ml of triethylamine are added to 50 ml of DMF and dissolved, and to this solution is added dropwise 0.65 ml of isobutyl chloroformate under external ice cooling and agitation. Thereafter, the mixture is agitated at room temperature for 30 minutes and then 0.8 ml of N-methyl-2-methylcyclohexylamine is added dropwise thereto, followed by additional 3-hour agitation. After the reaction, the solvent is distilled off and the residue is dissolved in 300 ml of chloroform, washed with diluted hydrochloric acid, diluted aqueous K₂ CO₃ solution and water in that order and then dried with anhydrous Na₂ SO₄. After filtering out the inorganic matter, the residue is recrystallized from benzene-ligroin, resultantly obtaining 0.4 g of colorless needle-like crystals of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril with melting point of 146°-149° C.

EXAMPLE 75

2.6 Grams of 1-methyl-6-(3-carboxypropoxy)-3,4-dihydrocarbostyril and 1.8 ml of pyridine are added to 50 ml of tetrahydrofuran, and then 1.0 ml of methyl bromoformate is added dropwise to this solution under external ice cooling and agitation while maintaining the internal temperature at 5° to 15° C. After this dropwise addition, the mixture is agitated at room temperature for 2 hours, added with 1.2 g of N-methylcyclohexylamine and further agitated for 3 hours. The reaction liquid is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The thus obtained crude crystals are recrystallized from ligroin to obtain 2.1 g of 1-methyl-6-[3-(N-cyclohexyl)-N-methylaminocarbonylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals, m.p. 104.5°-106.5° C.

EXAMPLE 76

2.6 Grams of 6-(3-carboxy-2-methylpropoxy)-carbostyril and 1.4 g of potassium carbonate are added to 50 ml of dimethylformamide, followed by dropwise addition of 1.1 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. After this dropwise addition, the mixture is agitated at 30° to 40° C. for 2 hours and then added with 1.6 ml of N-methyl-2-methylcyclohexylamine, followed by additional 2-hour agitation at the same temperature. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from benzene-ligroin to obtain 0.9 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)-aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals. m.p., 146°-149° C.

EXAMPLE 77

2.6 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 200 ml of ethyl acetate, followed by dropwise addition of 1.0 ml of ethyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. Thereafter, the mixture is agitated at room temperature for 1 hour, added with 1.4 g of N-ethylcyclohexylamine and further agitated for 1.5 hours. The reaction solution is poured into water to separate the liquid, and the organic layer is washed with dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na₂ SO₄. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene, obtaining 1.5 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 114°-115.5° C.

EXAMPLES 78-105

The compounds shown in Table 8 below are obtained from the reactions same as practiced in Examples 73-77.

                                      TABLE 8                                      __________________________________________________________________________      ##STR85##                                                                      No.Example                                                                            side chainstitutedof the sub-Position                                                R.sup.1                                                                                ##STR86##                                                                               R.sup.4       R.sup.5                                                                               formCrystal                                                                          (°C.)poin                                                              tMelting              __________________________________________________________________________     78     5     H       CH.sub.2                                                                                 ##STR87##    H      Pale- yellowish                                                                crystals                                                                             286- 288.5                                                                     (decom- posed)        79     5     CH.sub.3                                                                               "                                                                                        ##STR88##    H      Colorless needle-like                                                          crystals                                                                             186- 187              80     5     CH.sub.2 CHCH.sub.2                                                                     ##STR89##                                                                               ##STR90##    H      Colorless needle-like                                                          crystals                                                                             141.5- 142            81     5     H       "                                                                                        ##STR91##    H      Colorless needle-like                                                          crystals                                                                             186- 189              82     5     H       "                                                                                        ##STR92##    H      Colorless needle-like                                                          crystals                                                                             223- 226              83     5     H       "                                                                                        ##STR93##    H      Colorless flake-like                                                           crystals                                                                             211- 212              84     5     H                                                                                       ##STR94##                                                                               ##STR95##    C.sub.2 H.sub.5                                                                       Colorless needle-like                                                          crystals                                                                             159- 161              85     5     H       "                                                                                        ##STR96##    H      Colorless needle-like                                                          crystals                                                                             247- 248.5                                                                     (decom- posed)        86     5     H       (CH.sub.2).sub.2                                                                         ##STR97##    H      Colorless needle-like                                                          crystals                                                                             190.5- 192            87     5     H       (CH.sub.2).sub.3                                                                         ##STR98##    H      Colorless needle-like                                                          crystals                                                                             207- 208.5            88     5     H       "                                                                                        ##STR99##    H      Colorless needle-like                                                          crystals                                                                             270- 274 (decom-                                                               osed)                 89     5     H       "                                                                                        ##STR100##   H      Colorless needle-like                                                          crystals                                                                             212- 213              90     5     H       "                                                                                        ##STR101##   CH.sub.3                                                                              Colorless needle-like                                                          crystals                                                                             169- 172              91     5     C.sub.2 H.sub.5                                                                        "                                                                                        ##STR102##   H      Colorless needle-like                                                          crystals                                                                             122.5- 124            92     5     "       "                                                                                        ##STR103##   H      Colorless needle-like                                                          rystals                                                                              141.5- 143            93     5     H       (CH.sub.2).sub.6                                                                         ##STR104##                                                                                   ##STR105##                                                                           Colorless needle-like                                                          crystals                                                                             49- 52                94     5     H                                                                                       ##STR106##                                                                              ##STR107##   H      Colorless needle-like                                                          crystals                                                                             181- 182.5            95     6     H       (CH.sub.2).sub.3                                                                         ##STR108##   H      Colorless needle-like                                                          crystals                                                                             211.5- 213            96     6     H       "                                                                                        ##STR109##   CH.sub.3                                                                              Colorless needle-like                                                          crystals                                                                             129.5- 132.5          97     6     H       "                                                                                        ##STR110##   "      Colorless crystals                                                                   31- 35                98     6     CH.sub.2 CHCH.sub.2                                                                    (CH.sub.2).sub.6                                                                         ##STR111##   H      Colorless needle-like                                                          crystals                                                                             104-  105.5           99     7     H                                                                                       ##STR112##                                                                              ##STR113##   H      Colorless needle-like                                                          crystals                                                                             182.5- 183            100    5     H       (CH.sub.2).sub.3                                                                         ##STR114##   H      Colorless needle-like                                                          crystals                                                                             236- 239 (decom-                                                               osed)                 101    5     H                                                                                       ##STR115##                                                                              ##STR116##   H      Colorless needle-like                                                          crystals                                                                             156- 158              102    6     H       (CH.sub.2).sub.3                                                                         ##STR117##                                                                                   ##STR118##                                                                           Colorless needle-like                                                          crystals                                                                             160- 161              103    6     H       "                                                                                        ##STR119##                                                                                   ##STR120##                                                                           Colorless needle-like                                                          crystals                                                                             166- 168              104    6     H       "                                                                                        ##STR121##   H      Colorless needle-like                                                          crystals                                                                             298- 299 (decom-                                                               osed)                 105    6     H       "                                                                                        ##STR122##   H      Colorless crystals                                                                   235- 238              __________________________________________________________________________

EXAMPLES 106-139

The compounds of Table 9 below are obtained from the reactions same as performed in Examples 73-77.

                                      TABLE 9                                      __________________________________________________________________________      ##STR123##                                                 (1-2)               No.ampleEx-                                                                         side-chainstitutedof the sub-Position                                                R.sup.1                                                                                ##STR124##                                                                              R.sup.4       R.sup.5  formCrystal                                                                          (°C.)poin                                                              tMelting              __________________________________________________________________________     106  5     H       CH.sub.2                                                                                 ##STR125##   H        Yellowish plate-like                                                           crystals                                                                             183- 186              107  5     H       "                                                                                        ##STR126##   H        Colorless plate-like                                                           crystals                                                                             181.5- 185            108  5     H       "                                                                                        ##STR127##   H        Colorless needle-like                                                          crystals                                                                             202- 204.5            109  5     CH.sub.3                                                                                ##STR128##                                                                              ##STR129##   H        Colorless needle-like                                                          crystals                                                                             189- 190              110  5     H       (CH.sub.2).sub.3                                                                         ##STR130##   H        Colorless flake-like                                                           crystals                                                                             168.5- 171            111  5     H       "                                                                                        ##STR131##   H        Colorless flake-like                                                           crystals                                                                             236.5- 237                                                                     (decom- posed)        112  6     H                                                                                       ##STR132##                                                                              ##STR133##   CH.sub.3 Colorless plate-like                                                           crystals                                                                             172- 176              113  6     H       (CH.sub.2).sub.3                                                                         ##STR134##   H        Colorless needle-like                                                          crystals                                                                             255- 257              114  6                                                                                     ##STR135##                                                                            "                                                                                        ##STR136##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             107.5- 108.5          115  6     H       "                                                                                        ##STR137##   "        Colorless needle-like                                                          crystals                                                                             199- 201              116  6     H       (CH.sub.2).sub.3                                                                         ##STR138##   H        Colorless crystals                                                                   202.5- 206            117  6     H       "                                                                                        ##STR139##   H        Colorless crystals                                                                   268- 269              118  6     H       "                                                                                        ##STR140##   H        Colorless needle-like                                                          crystals                                                                             184- 185              119  6     CH.sub.3                                                                               "                                                                                        ##STR141##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             118.5- 119.5          120  6     H       "                                                                                        ##STR142##                                                                                   ##STR143##                                                                             Colorless needle-like                                                          crystals                                                                             185.5- 187            121  6     H       "                                                                                        ##STR144##   CH.sub.3 Colorless crystals                                                                   187-  190             122  6     H       (CH.sub.2).sub.3                                                                         ##STR145##   C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             150.5- 153            123  6     H       "                                                                                        ##STR146##                                                                                   ##STR147##                                                                             Colorless needle-like                                                          crystals                                                                             163.5- 164.5          124  6     H                                                                                       ##STR148##                                                                              ##STR149##   CH.sub.2 CH.sub.2 CH.sub.3                                                              Colorless plate-like                                                           crystals                                                                             134.5- 137.5          125  6     H                                                                                       ##STR150##                                                                              ##STR151##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             188- 190 (decom-                                                               osed)                 126  8     H       CH.sub.2                                                                                 ##STR152##   H        Colorless needle-like                                                          crystals                                                                             192.5- 193.5          127  6     H       (CH.sub.2).sub.3                                                                         ##STR153##   H        Colorless needle-like                                                          crystals                                                                             122- 124              128  6     H       "                                                                                        ##STR154##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             137- 140              129  6     H       "                                                                                        ##STR155##                                                                                   ##STR156##                                                                             Colorless crystals                                                                   78- 81                130  6     H       "                                                                                        ##STR157##   H        Pale yellowish                                                                 crystals                                                                             157- 160              131  6     H       "                                                                                        ##STR158##   H        Colorless needle-like                                                          crystals                                                                             105- 109              132  6     H                                                                                       ##STR159##                                                                              ##STR160##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             180- 182              133  6     H                                                                                       ##STR161##                                                                              ##STR162##   H        Colorless needle-like                                                          crystals                                                                             201- 203              134  6     H       (CH.sub.2).sub.3                                                                         ##STR163##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             127.5- 129.5          135  6     H       "                                                                                        ##STR164##   C.sub.2 H.sub.5                                                                         Colorless rhombic                                                              crystals                                                                             105- 107              136  6     H       "                                                                                        ##STR165##   C.sub.2 H.sub.                                                                          Colorless needle-like                                                          crystals                                                                             166.5- 168            137  6     H       "                                                                                        ##STR166##   (CH.sub.2).sub.7 CH.sub.3                                                               Colorless needle-like                                                          crystals                                                                             127- 128.5            138  6     H       "                                                                                        ##STR167##   (CH.sub.2).sub.7 CH.sub.3                                                               Colorless crystals                                                                   63.5- 66.0            139  6     H       "                                                                                        ##STR168##   (CH.sub.2).sub.7 CH.sub.3                                                               Colorless crystals                                                                   86.0- 89.5            __________________________________________________________________________

EXAMPLE 140

The procedure of Example 77 is repeated by using a suitable starting material to obtain 6-{3-[N-benzyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]-propoxy}-3,4-dihydrocarbostyril. This compound is identified by the following physicochemical properties.

State: Colorless oil

Silica gel thin-layer chromatography: (Silica gel: "Silica Gel 60 F-254" manufactured by Merck & Co., Inc.); Developing solvent: A mixture of chloroform-methanol [8:1 (vol/vol)], Rf=0.65

Elemental analysis: Calcd. for C₃₀ H₃₄ N₂ O₅ : C, 71.69%; H, 6.82%; N, 5.57%; Found: C, 71.84%; H, 6.75%; N, 5.29%

Nuclear magnetic resonance spectrum (NMR): δCDCl₃ =1.9-3.1 ppm (10H, m), 3.4 ppm (2H, t), 3.7-4.0 ppm (8H, m), 4.4 ppm (2H, d), 6.4-6.7 ppm (6H, m), 6.9-7.3 ppm (7H, m), 9.3 ppm (1H, br.)

The 6.9-7.3 ppm signal overlaps with the CHCl₃ proton signal.

Infrared absorption spectrum (IR): (ν_(max) ^(film) (cm⁻¹)=3220, 3002, 2940, 2840, 1670, 1638, 1595, 1500, 1450, 1360, 1240, 1157, 1013, 960, 850, 800, 740

EXAMPLE 141

5.0 Grams of 5-chloro-6-(3-carboxypropoxy)carbostyril and 2.97 ml of triethylamine are added to 100 ml of DMF, followed by dropwise addition thereto of 2.33 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 0° to 10° C. After this dropwise addition, the mixture is agitated at room temperature for 1 hour, added dropwise with 2.8 g of N-n-butylcyclohexylamine and further agitated at room temperature for 3 hours. After the reaction, the solvent is distilled off and the residue is dissolved in 600 ml of chloroform, washed with diluted hydrochloric acid, aqueous K₂ CO₃ solution and water in that order and then dried with anhydrous Na₂ SO₄. After removing the inorganic matter by filtration, the mother liquor is concentrated and the residue is recrystallized from ethanol, resultantly obtaining 2.5 g of 5-chloro-6-[3-N-cyclohexyl-N-butylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals. m.p., 178.5°-179.5° C.

EXAMPLES 142-179

The compounds shown in Table 10 below are obtained by the method similar to Example 141. In Table 10, the respective compounds are expressed by the symbols shown in the following general formula (1-3):

                                      TABLE 10                                     __________________________________________________________________________      ##STR169##                                                                       Posi-                                                                          tion                                                                           of                                                                             the                                                                               Bond-                                                                       sub-                                                                              ing           Posi-                                                         sti-                                                                              at 3-         tion(s)                                Melt-                No.Ex.                                                                            tuted side- chain                                                                 and 4- posi- tions                                                                 R.sup.1                                                                           (R.sup.2).sub.m                                                                       of the R.sup.2 sub- stituted                                                       ##STR170##                                                                              R.sup.4       R.sup.5                                                                               Crystal form                                                                        ing point                                                                     (°C.)        __________________________________________________________________________     142                                                                               5  Single bond                                                                        H  Br     8   CH.sub.2                                                                                 ##STR171##   H      Colorless needle-                                                              like crystals                                                                       212- 212.5          143                                                                               5  Single bond                                                                        H  Br     "   "                                                                                        ##STR172##   H      Colorless needle-                                                              like crystals                                                                       258- 259.5          144                                                                               5  Single bond                                                                        H  Br     "   (CH.sub.2).sub.3                                                                         ##STR173##   CH.sub.3                                                                              Colorless needle-                                                              like crystals                                                                       134- 135            145                                                                               5  Single bond                                                                        H  Br     "   "                                                                                        ##STR174##   H      Colorless needle-                                                              like crystals                                                                       260.5- 261                                                                     (decom-                                                                        posed)              146                                                                               5  Single bond                                                                        H  I      "   "                                                                                        ##STR175##   H      Colorless needle-                                                              like crystals                                                                       190- 191            147                                                                               5  Single bond                                                                        H  (I).sub.2                                                                             6 8 "                                                                                        ##STR176##   (CH.sub.2).sub.3 CH.sub.3                                                             Colorless needle-                                                              like crystals                                                                       109.5- 110.5        148                                                                               5  Single bond                                                                        H  (Cl).sub.2                                                                            6 8 "                                                                                        ##STR177##   C.sub.2 H.sub.5                                                                       Colorless rhombic                                                              crystals                                                                            130- 132            149                                                                               5  Single bond                                                                        H  (Cl).sub.2                                                                            6 8 "                                                                                        ##STR178##   H      Colorless needle-                                                              like crystals                                                                       270- 271                                                                       (decom-                                                                        posed)              150                                                                               6  Double bond                                                                        H  Cl     5   CH.sub.2                                                                                 ##STR179##   H      Colorless needle-                                                              like crystals                                                                       225- 226            151                                                                               6  Double bond                                                                        H  Cl     "   "                                                                                        ##STR180##   H      Colorless needle-                                                              like crystals                                                                       311.5-  313                                                                    (decom-                                                                        posed)              152                                                                               6  Double bond                                                                        H  Cl     "   (CH.sub.2).sub.3                                                                         ##STR181##   CH.sub.3                                                                              Colorless needle-                                                              like crystals                                                                       179- 180.5          153                                                                               6  Double bond                                                                        H  Cl     "   "                                                                                        ##STR182##   "      Colorless needle-                                                              like crystals                                                                       191.5- 193          154                                                                               6  Double bond                                                                        CH.sub.3                                                                          Cl     "   "                                                                                        ##STR183##   "      Pale- yellowish                                                                needle- like                                                                   crystals                                                                            137- 138            155                                                                               6  Double bond                                                                        H  Cl     "   "                                                                                        ##STR184##   C.sub.2 H.sub.5                                                                       Colorless needle-                                                              like crystals                                                                       134.5- 136          156                                                                               8  Single bond                                                                        H  (Cl).sub.3                                                                            5 6 7                                                                              "                                                                                        ##STR185##   CH.sub.3                                                                              Colorless needle-                                                              like crystals                                                                       131- 132.5          157                                                                               5  Single bond                                                                        H  OH     8   "                                                                                        ##STR186##   "      Colorless crystals                                                                  119- 121            158                                                                               5  Single bond                                                                        H  "      "   "                                                                                        ##STR187##   CH.sub.2 CH.sub.2 CH.sub.3                                                            Colorless crystals                                                                  116- 117            159                                                                               5  Single bond                                                                        H                                                                                  ##STR188##                                                                           "   "                                                                                        ##STR189##   CH.sub.3                                                                              Colorless prism                                                                crystals                                                                            106.5- 110          160                                                                               5  Single bond                                                                        H  "      "   "                                                                                        ##STR190##   CH.sub.2 CH.sub.2 CH.sub.3                                                            Colorless plate-                                                               like crystals                                                                       88- 90.5            __________________________________________________________________________

EXAMPLE 161

3.7 Grams of 6-[3-(p-nitrophenoxycarbonyl)propoxy]-carbostryil is dissolved in 40 ml of dimethylformamide, and the mixed solution is further added with 2.0 g of cyclohexylamine and allowed to stand overnight at room temperature. The reaction solution is concentrated under reduced pressure and evaporated to dryness, and the obtained residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: chloroform) and then recrystallized from ethanol) to obtain 1.5 g of 6-[3-(N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 251°-252° C.

EXAMPLE 162

3.8 Grams of 6-[3-(p-nitrophenoxycarbonyl)-2-methylpropoxy]carbostyril is dissolved in 40 ml of dimethylformamide, followed by addition of 1.6 ml of N-methyl-2-methylcyclohexylamine and 12-hour agitation at 60°-70° C. After the reaction, the solvent is distilled off and the obtained residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 20/1 (V/V) chloroform/methanol) and the crude crystals are recrystallized from benzene-ligroin to obtain 1.6 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needlelike crystals with melting point of 146°-149° C.

EXAMPLES 163-204

The compounds in Tables 11 to 13 below are obtained according to the procedure of Examples 161-162.

The respective compounds in Table 11, Table 12 and Table 13 are expressed by the symbols given in the afore-shown general formulae (1-1), (1-2) and (1-3), respectively.

                                      TABLE 11                                     __________________________________________________________________________      ##STR191##                                                                     No.Example                                                                           side-chainstitutedthe sub-Position of                                                R.sup.1                                                                                ##STR192##                                                                              R.sup.4       R.sup.5  formCrystal                                                                          (°C.)poi                                                               ntMelting            __________________________________________________________________________     163   5     H       CH.sub.2                                                                                 ##STR193##   H        Pale- yellowish                                                                crystals                                                                             286- 288.5                                                                     (decom- posed        164   5     CH.sub.2 CHCH.sub.2                                                                     ##STR194##                                                                              ##STR195##   H         Colorless needle-like                                                          crystals                                                                            141.5- 142           165   5     H       "                                                                                        ##STR196##   H        Colorless flake-like                                                           crystals                                                                             211- 212             166   5     H       (CH.sub.2).sub.3                                                                         ##STR197##   H        Colorless needle-like                                                          rystals                                                                              207- 208.5           167   5     H                                                                                       ##STR198##                                                                              ##STR199##   C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          rystals                                                                              114- 115.5           168   5     H       (CH.sub.2).sub.6                                                                         ##STR200##                                                                                   ##STR201##                                                                             Colorless needle-like                                                          rystals                                                                              49- 52               169   6     H       (CH.sub.2).sub.3                                                                         ##STR202##   H        Colorless needle-like                                                          rystals                                                                              211.5- 213           170   6     CH.sub.3                                                                               "                                                                                        ##STR203##   CH.sub.3 Colorless needle-like                                                          rystals                                                                              104.5- 106.5         171   6     H       "                                                                                        ##STR204##   "        Colorless crystals                                                                   31- 35               172   6     CH.sub.2 CHCH.sub.2                                                                    (CH.sub.2).sub.6                                                                         ##STR205##   H        Colorless needle-like                                                          rystals                                                                              104- 105.5           173   7     H                                                                                       ##STR206##                                                                              ##STR207##   H        Colorless needle-like                                                          rystals                                                                              182.5- 183           174   5     H       (CH.sub.2).sub.3                                                                         ##STR208##   CH.sub.3 Colorless rhombic                                                              crystals                                                                             133- 134             175   6     H       (CH.sub.2).sub.3                                                                         ##STR209##   CH.sub.2 CHCH.sub.2                                                                     Colorless needle-like                                                          rystals                                                                              105- 107             176   6     H       "                                                                                        ##STR210##                                                                                   ##STR211##                                                                             Colorless needle-like                                                          rystals                                                                              182- 184             177   6     H       (CH.sub.2).sub.4                                                                         ##STR212##   (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like                                                          rystals                                                                              109.5-  111.5        178   6     H       "                                                                                        ##STR213##   H        Colorless needle-like                                                          rystals                                                                              183- 184.5           __________________________________________________________________________

                                      TABLE 12                                     __________________________________________________________________________      ##STR214##                                                                     No.Example                                                                          side-chainstitutedthe sub-Position of                                                R.sup.1                                                                               ##STR215##                                                                              R.sup.4    R.sup.5  formCrystyal                                                                         (°C.)pointMel                                                          ting                      __________________________________________________________________________     179  5     CH.sub.3                                                                               ##STR216##                                                                              ##STR217##                                                                               H        Colorless needle-like                                                          crystals                                                                             189- 190                  180  5     H      CH.sub.2                                                                                 ##STR218##                                                                               H        Colorless needle-like                                                          crystals                                                                             202- 204.5                181  6     H                                                                                      ##STR219##                                                                              ##STR220##                                                                               CH.sub.3 Colorless needle-like                                                          crystals                                                                             188- 190 (decom-                                                               posed)                    182  6     H      (CH.sub.2).sub.3                                                                         ##STR221##                                                                               "        Colorless crystals                                                                   187- 190                  183  6     H      "                                                                                        ##STR222##                                                                               C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             150.5- 153                184  6     H      "                                                                                        ##STR223##                                                                                ##STR224##                                                                             Colorless needle-like                                                          crystals                                                                             163.5- 164.5              185  6     H      "                                                                                        ##STR225##                                                                               H        Colorless needle-like                                                          crystals                                                                             255- 257                  186  6                                                                                     ##STR226##                                                                           "                                                                                        ##STR227##                                                                               CH.sub.3 Colorless needle-like                                                          crystals                                                                             107.5- 108.5              187  6     H      "                                                                                        ##STR228##                                                                               "        Colorless needle-like                                                          crystals                                                                             199- 201                  188  6     H      "                                                                                        ##STR229##                                                                               H        Colorless crystals                                                                   202.5- 206                189  6     CH.sub.3                                                                              "                                                                                        ##STR230##                                                                               CH.sub.3 Colorless needle-like                                                          crystals                                                                             118.5- 119.5              190  6     H      (CH.sub.2).sub.3                                                                         ##STR231##                                                                                ##STR232##                                                                             Colorless needle-like                                                          crsytals                                                                             185.6- 187                191  6     H                                                                                      ##STR233##                                                                              ##STR234##                                                                               CH.sub.3 Colorless plate-like                                                           crystals                                                                             172- 176                  192  8     H      CH.sub.2                                                                                 ##STR235##                                                                               H        Colorless needle-like                                                          crystals                                                                             192.5- 193.5              193  6     H      (CH.sub.2).sub.3                                                                         ##STR236##                                                                                ##STR237##                                                                             Colorless needle-like                                                          crystals                                                                             180- 181.5                194  6     H      "                                                                                        ##STR238##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like                                                          crystals                                                                             159-  160                 __________________________________________________________________________

                                      TABLE 13                                     __________________________________________________________________________      ##STR239##                                                                     No.Ex.                                                                            chainside-stitutedsub-of thePosition                                                tionsposi-and 4-at 3-Bonding                                                        R.sup.1                                                                           (R.sup.2).sub.m                                                                       R.sup.2 groupstitutedsub-of thetion(s)Posi-                                         ##STR240##                                                                              R.sup.4  R.sup.5                                                                                formCrystal                                                                         (°C.)po                                                                intingMelt-         __________________________________________________________________________     195                                                                               5    Single  bond                                                                        H  Br     8    CH.sub.2                                                                                 ##STR241##                                                                             H       Colorless needle-                                                              like crystals                                                                       212- 212.5          196                                                                               5    Single bond                                                                         H  (I).sub.2                                                                             6 8  (CH.sub.2).sub.3                                                                         ##STR242##                                                                             (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-                                                              like crystals                                                                       109.5- 110.5        197                                                                               8    Single bond                                                                         H  (Cl).sub.3                                                                            5 6 7                                                                               (CH.sub.2).sub.3                                                                         ##STR243##                                                                             CH.sub.3                                                                               Colorless needle-                                                              like crystals                                                                       131- 132.5          198                                                                               5    Single bond                                                                         H  (Cl).sub.2                                                                            6 8  (CH.sub.2).sub.3                                                                         ##STR244##                                                                             C.sub.2 H.sub.5                                                                        Colorless rhombic                                                              crystals                                                                            130- 132            199                                                                               5    Single bond                                                                         H                                                                                  ##STR245##                                                                           8    "                                                                                        ##STR246##                                                                             CH.sub.3                                                                               Colorless prism-                                                               like crystals                                                                       106.5- 110          200                                                                               6     Double bond                                                                        H  Cl     5    CH.sub.2                                                                                 ##STR247##                                                                             H       Colorless needle-                                                              like crystals                                                                       225- 226            201                                                                               6    Double bond                                                                         H  Cl     "    "                                                                                        ##STR248##                                                                             H       Colorless needle-                                                              like crystals                                                                       311.5- 313                                                                     (de- com-                                                                      posed)              202                                                                               6    Double bond                                                                         H  Cl     "    (CH.sub.2).sub.3                                                                         ##STR249##                                                                             CH.sub.3                                                                               Colorless needle-                                                              like crystals                                                                       191.5- 193          203                                                                               6    Double bond                                                                         CH.sub.3                                                                          Cl     "    "                                                                                        ##STR250##                                                                             "       Pale- yellowish                                                                needle- like                                                                   crystals                                                                            137- 138            204                                                                               5    Single bond                                                                         H  OH     8    (CH.sub.2).sub.3                                                                         ##STR251##                                                                             CH.sub.2 CH.sub.2 CH.sub.3                                                             Colorless crystals                                                                  116- 117            __________________________________________________________________________

EXAMPLE 205

2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.2 g of N-methylcyclohexylamine are added to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride, and to this mixture is added dropwise a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide in 5 ml of methylene chloride maintained at 10°-20° C. under external ice cooling and agitation, followed by additional 3.5-hour agitation at the same temperature. The precipitated crystals are filtered out and the filtrate is concentrated under reduced pressure and evaporated to dryness. The obtained residue is dissolved in 100 ml of methylene chloride and the organic layer is washed with a 5% aqueous solution of hydrochloric acid, a 5% aqueous solution of sodium carbonate and water in that order and then dried with anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is recrystallized from chloroform-ethanol to obtain 1.9 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril in the form of colorless needle-like crystals with melting point of 184.5°- 186° C.

EXAMPLE 206

To a solution of 2.9 g of 5-(6-carboxyhexyloxy)-3,4-dihydrocarbostyril and 1.9 g of N-benzylcyclohexylamine in 100 ml of DMF is added gradually dropwise a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide in 10 ml of DMF at room temperature and under agitation. After this agitation, the mixture is further agitated at room temperature for 5 hours. After the reaction, the insolubles are filtered off and the mother liquor is concentrated. The residue is dissolved in chloroform and subjected to silica gel thin-layer chromatography (solvent: chloroform-methanol (8:1) to scrape out the portion with Rf value of 0.8. The silica gel is extracted with chloroform, and after distilling off chloroform, the residue is recrystallized from benzene-ligroin to obtain 1.1 g of 5-[6-(N-cyclohexyl-N-benzylaminocarbonyl)hexyloxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 49°-52° C.

EXAMPLES 207-243

The compounds shown in Tables 14-16 below are obtained by following the same procedure as Examples 205 and 206. The respective compounds in Table 14, Table 15 and Table 16 are expressed by the symbols given in the aforeshown general formulae (1-1); (1-2) and (1-3), respectively.

                                      TABLE 14                                     __________________________________________________________________________      ##STR252##                                                                     No.Example                                                                           side-chainstitutedthe sub-Position of                                                R.sup.1                                                                                ##STR253##                                                                              R.sup.4       R.sup.5  formCrystal                                                                          (°C.)poi                                                               ntMelting            __________________________________________________________________________     207   5     H       CH.sub.2                                                                                 ##STR254##   H        Pale- yellowish                                                                crystals                                                                             286- 288.5                                                                     (decom- posed)       208   5     CH.sub.2 CHCH.sub.2                                                                     ##STR255##                                                                              ##STR256##   H        Colorless needle-like                                                          rystals                                                                              141.5- 142           209   5     H       (CH.sub.2).sub.3                                                                         ##STR257##   H        Colorless needle-like                                                          rystals                                                                              207- 208.5           210   5     H                                                                                       ##STR258##                                                                              ##STR259##   C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          rystals                                                                              114- 115.5           211   6     H       (CH.sub.2).sub.3                                                                         ##STR260##   CH.sub.3 Colorless crystals                                                                   31- 35               212   6     CH.sub.3                                                                               "                                                                                        ##STR261##   CH.sub.3 Colorless needle-like                                                          rystals                                                                              104.5- 106.5         213   6     H       "                                                                                        ##STR262##   H        Colorless needle-like                                                          rystals                                                                              211.5- 213           214   6     CH.sub.2 CHCH.sub.2                                                                    (CH.sub.2).sub.6                                                                         ##STR263##   H        Colorless  needle-like                                                          crystals                                                                            104- 105.5           215   7     H                                                                                       ##STR264##                                                                              ##STR265##   H        Colorless needle-like                                                          rystals                                                                              182.5- 183           216   6     H       (CH.sub.2).sub.3                                                                         ##STR266##   CH.sub.2 CHCH.sub.2                                                                     Colorless needle-like                                                          rystals                                                                              105- 107             217   6     H       "                                                                                        ##STR267##                                                                                   ##STR268##                                                                             Colorless needle-like                                                          rystals                                                                              182- 184             __________________________________________________________________________

                                      TABLE 15                                     __________________________________________________________________________      ##STR269##                                                                     No.Example                                                                          side-chainstitutedthe sub-Position of                                                R.sup.1                                                                               ##STR270##                                                                              R.sup.4   R.sup.5  formCrystal                                                                          Melting  point                                                                (°C.)               __________________________________________________________________________     218  5     CH.sub.3                                                                               ##STR271##                                                                              ##STR272##                                                                              H        Colorless needle-like                                                          crystals                                                                             189- 190                   219  5     H      CH.sub.2                                                                                 ##STR273##                                                                              H        Colorless needle-like                                                          crystals                                                                             202- 204.5                 220  8     H      "                                                                                        ##STR274##                                                                              H        Colorless needle-like                                                          crystals                                                                             192.5- 193.5               221  6     H                                                                                      ##STR275##                                                                              ##STR276##                                                                              CH.sub.3 Colorless plate-like                                                           crystals                                                                             172- 176                   222  6     H      (CH.sub.2).sub.3                                                                         ##STR277##                                                                              C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             150.5- 153                 223  6                                                                                     ##STR278##                                                                           "                                                                                        ##STR279##                                                                              CH.sub.3 Colorless needle-like                                                          crystals                                                                             107.5- 108.5               224  6     H      "                                                                                        ##STR280##                                                                              CH.sub.3 Colorless crystals                                                                   187- 190                   225  6     H      "                                                                                        ##STR281##                                                                              H        Colorless crystals                                                                   202.5- 206                 226  6     CH.sub.3                                                                              "                                                                                        ##STR282##                                                                              CH.sub.3 Colorless needle-like                                                          crystals                                                                             118.5- 119.5               227  6     H      "                                                                                        ##STR283##                                                                               ##STR284##                                                                             Colorless needle-like                                                          crystals                                                                             185.5- 187                 228  6     H      "                                                                                        ##STR285##                                                                               ##STR286##                                                                             Colorless needle-like                                                          crystals                                                                             163.5- 164.5               229  6     H                                                                                      ##STR287##                                                                              ##STR288##                                                                              CH.sub.3 Colorless needle-like                                                          crystals                                                                             146- 149                   230  6     H                                                                                      ##STR289##                                                                              ##STR290##                                                                              CH.sub.3 Colorless needlelike-                                                          crystals                                                                             188- 190 (decom-                                                               posed)                     231  6     H      (CH.sub.2 ).sub.3                                                                        ##STR291##                                                                              CH.sub.3 Colorless needle-like                                                          crystals                                                                             143- 143.5                 232  6     H      "                                                                                        ##STR292##                                                                               ##STR293##                                                                             Colorless needle-like                                                          crystals                                                                             180- 181.5                 233  6     H      (CH.sub.2 ).sub.4                                                                        ##STR294##                                                                              (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like                                                          crystals                                                                             151- 153.5                 __________________________________________________________________________

                                      TABLE 16                                     __________________________________________________________________________      ##STR295##                                                                     No.ampleEx-                                                                        chainside-stitutedsub-of thePosition                                                tionsposi-and 4-at 3-Bonding                                                        R.sup.1                                                                           (R.sup.2).sub.m                                                                       R.sup.2 groupstitutedsub-of thetion(s)Posi-                                         ##STR296##                                                                              R.sup.4  R.sup.5                                                                              formCrystal                                                                         (°C.)poi                                                               ntMelting            __________________________________________________________________________     234 5    Single  bond                                                                        H  Br     8    CH.sub.2                                                                                 ##STR297##                                                                             H     Colorless needle-                                                              like crystals                                                                       212- 212.5           235 5    Single bond                                                                         H  (I).sub.2                                                                             6 8  (CH.sub.2).sub.3                                                                         ##STR298##                                                                             (CH.sub.2).sub.3 CH.sub.3                                                            Colorless needle-                                                              like crystals                                                                       109.5- 110.5         236 8    Single bond                                                                         H  (Cl).sub.3                                                                            5 6 7                                                                               "                                                                                        ##STR299##                                                                             CH.sub.3                                                                             Colorless needle-                                                              like crystals                                                                       131- 132.5           237 5    Single bond                                                                         H  (Cl).sub.2                                                                            6 8  (CH.sub.2).sub.3                                                                         ##STR300##                                                                             C.sub.2 H.sub.5                                                                      Colorless rhombic                                                              crystals                                                                            130- 132             238 5    Single bond                                                                         H                                                                                  ##STR301##                                                                           8    "                                                                                        ##STR302##                                                                             (CH.sub.2).sub.2 CH.sub.3                                                            Colorless plate-                                                               like crystals                                                                        88- 90.5            239 6    Double bond                                                                         H  Cl     5    CH.sub.2                                                                                 ##STR303##                                                                             H     Colorless needle-                                                              like crystals                                                                       225- 226             240 6    Double bond                                                                         H  Cl     "    "                                                                                        ##STR304##                                                                             H     Colorless needle-                                                              like crystals                                                                       311.5- 313                                                                     (decom- posed)       241 6    Double bond                                                                         H  Cl     "    (CH.sub.2).sub.3                                                                         ##STR305##                                                                             CH.sub.3                                                                             Colorless needle-                                                              like crystals                                                                       191.5- 193           242 6    Double bond                                                                         CH.sub.3                                                                          Cl     "    "                                                                                        ##STR306##                                                                             "     Pale- yellowish                                                                needle- like                                                                   crystals                                                                            137- 138             243 5    Single bond                                                                         H  OH     8    "                                                                                        ##STR307##                                                                             "     Colorless crystals                                                                  119- 121             __________________________________________________________________________

EXAMPLE 244

2.7 Grams of 6-(3-ethoxycarbonyl-2-methylpropoxy)carbostyril, 0.5 g of sodium ethylate and 5 ml of N-methyl-2-methylcyclohexylamine are added to 100 ml of ethanol, and the mixture is reacted in an autoclave under 110 atm. and at 140° to 150° C. for 6 hours. After cooling, the reaction solution is concentrated under reduced pressure and the residue is dissolved in 200 ml of chloroform, washed with a 1% aqueous K₂ CO₃ solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na₂ SO₄. The solvent is distilled off and the residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 20/1 (V/V) chloroform-methanol) and the obtained crude crystals are recrystallized from benzene-ligroin, resultantly obtaining 1.0 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals with melting point of 146°-149° C.

EXAMPLES 245-283

The compounds of Tables 17-19 below are obtained by repeating the reaction process of Example 244. The respective compounds in Table 17, Table 18 and Table 19 are expressed by the symbols given in the general formulae (1-1), (1-2) and (1-3), respectively.

                                      TABLE 17                                     __________________________________________________________________________      ##STR308##                                                                     Example No.                                                                        Position of the sub- stituted side-chain                                              R.sup.1                                                                                ##STR309##                                                                              R.sup.4       R.sup.5  Crystal form                                                                         Melting point                                                                 (°C.)          __________________________________________________________________________     245    5   CH.sub.2 CHCH.sub.2                                                                     ##STR310##                                                                              ##STR311##   H        Colorless needle-like                                                          crystals                                                                             141.5-142             246    5   H                                                                                       ##STR312##                                                                              ##STR313##   H        Colorless flake-like                                                           crystals                                                                             211-212               247    5   H       (CH.sub.2 ).sub.3                                                                        ##STR314##   H        Colorless needle-like                                                          crystals                                                                             207-208.5             248    5   H                                                                                       ##STR315##                                                                              ##STR316##   C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             114-115.5             249    6   H       (CH.sub.2).sub.3                                                                         ##STR317##   CH.sub.3 Colorless crystals                                                                   31-35                 250    6   CH.sub.3                                                                               (CH.sub.2).sub.3                                                                         ##STR318##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             104.5-106.5           251    6   CH.sub.2 CHCH.sub.2                                                                    (CH.sub.2).sub.6                                                                         ##STR319##   H        Colorless needle-like                                                          crystals                                                                             104-105.5             252    7   H                                                                                       ##STR320##                                                                              ##STR321##   H        Colorless needle-like                                                          crystals                                                                             182.5-183             253    5   H       (CH.sub.2).sub.6                                                                         ##STR322##                                                                                   ##STR323##                                                                             Colorless needle-like                                                          crystals                                                                             49-52                 254    5   H       (CH.sub.2).sub.3                                                                         ##STR324##   CH.sub.2 CHCH.sub.2                                                                     Colorless needle-like                                                          crystals                                                                             116.5-118             255    6   H       (CH.sub.2).sub.3                                                                         ##STR325##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             144-146               256    6   H       (CH.sub.2).sub.3                                                                         ##STR326##                                                                                   ##STR327##                                                                             Colorless needle-like                                                          crystals                                                                             201-205               257    5   H       (CH.sub.2).sub.3                                                                         ##STR328##   H        Colorless needle-like                                                          crystals                                                                             211-212.5             258    6   H       (CH.sub.2).sub.3                                                                         ##STR329##                                                                                   ##STR330##                                                                             Colorless needle-like                                                          crystals                                                                             182-184               __________________________________________________________________________

                                      TABLE 18                                     __________________________________________________________________________      ##STR331##                                                                     Example No.                                                                        Position of the sub- stituted side-chain                                              R.sup.1                                                                               ##STR332##                                                                              R.sup.4  R.sup.5  Crystal form                                                                         Melting point                                                                 (°C.)                __________________________________________________________________________     259    5   H      CH.sub.2                                                                                 ##STR333##                                                                             H        Colorless needle-like                                                          crystals                                                                             202-204.5                   260    8   H      CH.sub.2                                                                                 ##STR334##                                                                             H        Colorless needle-like                                                          crystals                                                                             192.5-193.5                 261    6   H                                                                                      ##STR335##                                                                              ##STR336##                                                                             CH.sub.3  Colorless plate-like                                                          crystals                                                                             172-176                     262    6   H      (CH.sub.2).sub.3                                                                         ##STR337##                                                                             C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             150.5-153                   263    6                                                                                   ##STR338##                                                                           (CH.sub.2).sub.3                                                                         ##STR339##                                                                             CH.sub.3 Colorless needle-like                                                          crystals                                                                             107.5-108.5                 264    6   H      (CH.sub.2).sub.3                                                                         ##STR340##                                                                             H        Colorless crystals                                                                   202.5-206                   265    6   CH.sub.3                                                                              (CH.sub.2).sub.3                                                                         ##STR341##                                                                             CH.sub.3 Colorless needle-like                                                          crystals                                                                             118.5-119.5                 266    6   H      (CH.sub.2).sub.3                                                                         ##STR342##                                                                              ##STR343##                                                                             Colorless needle-like                                                          crystals                                                                             185.5-187                   267    6   H      (CH.sub.2).sub.3                                                                         ##STR344##                                                                              ##STR345##                                                                             Colorless needle-like                                                          crystals                                                                             163.5-164.5                 268    6   H                                                                                      ##STR346##                                                                              ##STR347##                                                                             CH.sub.3  Colorless needle-like                                                         crystals                                                                             188-190 (decom-                                                                posed)                      269    6   H      (CH.sub.2).sub.3                                                                         ##STR348##                                                                             H        Colorless needle-like                                                          crystals                                                                             251-252                     270    6   H      (CH.sub.2).sub.3                                                                         ##STR349##                                                                             CH.sub.3 Colorless needle-like                                                          crystals                                                                             184.5-186                   271    6   H      (CH.sub.2).sub.3                                                                         ##STR350##                                                                             (CH.sub.2).sub.3 CH.sub.3                                                               Colorless needle-like                                                          crystals                                                                             159-160                     272    6   H      (CH.sub.2).sub.3                                                                         ##STR351##                                                                             C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             115.5-117                   273    6   H      (CH.sub.2).sub.3                                                                         ##STR352##                                                                             H        Colorless needle-like                                                          crystals                                                                             222.5-224                   __________________________________________________________________________

                                      TABLE 19                                     __________________________________________________________________________      ##STR353##                                                                     Exam- ple No.                                                                     Position of the sub- stituted side- chain                                            Bonding at 3- and 4- posi- tions                                                    R.sup.1                                                                           (R.sup.2).sub.m                                                                      Posi- tion(s) of the sub- stituted R.sup.2                                           ##STR354##                                                                              R.sup.4  R.sup.5                                                                              Crystal form                                                                        Melting point                                                                 (°C.)         __________________________________________________________________________     274  5   Single bond                                                                         H  Br       8   CH.sub.2                                                                                ##STR355##                                                                             H     Colorless needle-                                                              like crystals                                                                       212- 212.5           275  5   Single bond                                                                         H  (I).sub.2                                                                               6 8                                                                               (CH.sub.2).sub.3                                                                         ##STR356##                                                                             (CH.sub.2).sub.3 CH.sub.3                                                            Colorless needle-                                                              like crystals                                                                       109.5- 110.5         276  8   Single bond                                                                         H  (Cl).sub.3                                                                              5 6 7                                                                             (CH.sub.2).sub.3                                                                         ##STR357##                                                                             CH.sub.3                                                                             Colorless needle-                                                              like crystals                                                                       131- 132.5           277  8   Single bond                                                                         H  (Cl).sub.2                                                                              6 8                                                                               (CH.sub.2).sub.3                                                                         ##STR358##                                                                             C.sub.2 H.sub.5                                                                      Colorless rhombic                                                              crystals                                                                            130- 132             278  5   Single bond                                                                         H                                                                                  ##STR359##                                                                             8  (CH.sub.2).sub.3                                                                         ##STR360##                                                                             CH.sub.3                                                                             Colorless prism-                                                               like crystals                                                                       106.5- 110           279  6   Double bond                                                                         H  Cl       5  CH.sub.2                                                                                 ##STR361##                                                                             H     Colorless needle-                                                              like crystals                                                                       225- 226             280  6   Double bond                                                                         H  Cl       5  CH.sub.2                                                                                 ##STR362##                                                                             H     Colorless needle-                                                              like crystals                                                                       311.5- 313                                                                     (decom- posed)       281  6   Double bond                                                                         H  Cl       5  (CH.sub.2).sub.3                                                                         ##STR363##                                                                             CH.sub.3                                                                             Colorless needle-                                                              like crystals                                                                       191.5- 193           282  6   Double bond                                                                         CH.sub.3                                                                          Cl       5  (CH.sub.2).sub.3                                                                         ##STR364##                                                                             CH.sub.3                                                                             Pale- yellowish                                                                needle- like                                                                   crystals                                                                            137- 138             283  5   Single bond                                                                         H  OH       8  (CH.sub.2).sub.3                                                                         ##STR365##                                                                             CH.sub.3                                                                             Colorless crystals                                                                  119- 121             __________________________________________________________________________

EXAMPLE 284

2.5 Grams of 6-(3-carboxypropoxy)carbostyril is suspended in 200 ml of chloroform, followed by addition of 1.5 ml of triethylamine, and then 1.2 g of thionyl chloride is added dropwise to the solution under agitation while maintaining the internal temperature at 0° to 20° C. After this addition, the mixture is agitated at the same temperature for 1 hour and then added dropwise with 2 ml of N-methylcyclohexylamine, followed by additional 3-hour agitation at room temperature. The reaction solution is washed well with a 5% aqueous K₂ CO₃ solution, then further washed with water and diluted hydrochloric acid and then dried with anhydrous Na₂ SO₄. After removing the solvent by distillation, the residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 10:1 chloroform/methanol (V/V)) and then recrystallized from chloroform-ethanol to obtain 0.4 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril with melting point of 184.5°-186° C.

EXAMPLE 285

2.6 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril is suspended in 200 ml of methylene chloride, followed by addition of 2 ml of pyridine. Then 1.4 g of thionyl chloride is added dropwise to this mixed solution while maintaining the internal temperature at 0° to 20° C. After the end of this addition, the mixture is further agitated at the same temperature for 1 hour and then added dropwise with 2 ml of N-ethylcyclohexylamine, followed by additional 4-hour agitation at room temperature. The reaction solution is washed well with an aqueous K₂ CO₃ solution and then with water and diluted hydrochloric acid and then dried with anhydrous Na₂ SO₄. Thereafter, the solvent is distilled off and the resultant residue is isolated and refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: chloroform-methanol (20:1 (V/V)) and then recrystallized from ligroinbenzene to obtain 0.6 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals, m.p., 114°-115.5° C.

EXAMPLES 286-316

The compounds shown in Tables 20-22 below are obtained by the method similar to Examples 284-285. The respective compounds in Table 20, Table 21 and Table 22 are expressed by the symbols given in the general formulae (1-1), (1-2) and (1-3), respectively.

                                      TABLE 20                                     __________________________________________________________________________      ##STR366##                                                                     Example No.                                                                        Position of the sub- stituted side-chain                                               R.sup.1                                                                                ##STR367##                                                                              R.sup.4       R.sup.5                                                                               Crystal form                                                                          Melting point                                                                 (°C.)          __________________________________________________________________________     286  5      H       CH.sub.2                                                                                 ##STR368##   H      Pale yellowish crystals                                                               286-288.5                                                                      (decom- posed)        287  5      CH.sub.2 CHCH.sub.2                                                                     ##STR369##                                                                              ##STR370##   H      Colorless needle-like                                                          crystals                                                                              141.5-142             288  5      H       (CH.sub.2).sub.3                                                                         ##STR371##   H      Colorless needle-like                                                          crystals                                                                              207-208.5             289  6      CH.sub.2 CHCH.sub.2                                                                    (CH.sub.2).sub.6                                                                         ##STR372##   H      Colorless needle-like                                                          crystals                                                                              104-105.5             290  5      H       (CH.sub.2).sub.6                                                                         ##STR373##                                                                                   ##STR374##                                                                           Colorless needle-like                                                          crystals                                                                              49-52                 291  6      CH.sub.3                                                                               (CH.sub.2).sub.3                                                                         ##STR375##   CH.sub.3                                                                              Colorless needle-like                                                          crystals                                                                              104.5-106.5           292  6      H       (CH.sub.2).sub.3                                                                         ##STR376##   CH.sub.3                                                                              Colorless crystals                                                                    31-35                 293  7      H                                                                                       ##STR377##                                                                              ##STR378##   H      Colorless needle-like                                                          crystals                                                                              182.5-183             294  6      H       (CH.sub.2).sub.3                                                                         ##STR379##                                                                                   ##STR380##                                                                           Colorless needle-like                                                          crystals                                                                              182-184               295  6      H       (CH.sub.2).sub.3                                                                         ##STR381##   (CH.sub.2).sub.3 CH.sub.3                                                             Colorless rhombic                                                              crystals                                                                              108-110               296  6      H       (CH.sub.2).sub.3                                                                         ##STR382##   CH.sub.3                                                                              Colorless needle-like                                                          crystals                                                                              144-146               __________________________________________________________________________

                                      TABLE 21                                     __________________________________________________________________________      ##STR383##                                                                     Example No.                                                                        Position of the sub- stituted side-chain                                               R.sup.1                                                                               ##STR384##                                                                               R.sup.4   R.sup.5    Crystal form                                                                          Melting point                                                                 (°C.)          __________________________________________________________________________     297  8      H      CH.sub.2                                                                                  ##STR385##                                                                              H          Colorless needle-like                                                          crystals                                                                              192.5-193.5           298  6      H                                                                                      ##STR386##                                                                               ##STR387##                                                                              CH.sub.3   Colorless plate-like                                                           crystals                                                                              172-176               299  6      H      (CH.sub.2).sub.3                                                                          ##STR388##                                                                              C.sub.2 H.sub.5                                                                           Colorless plate-like                                                           crystals                                                                              150.5-153             300  6      H      (CH.sub.2).sub.3                                                                          ##STR389##                                                                               ##STR390##                                                                               Colorless plate-like                                                           crystals                                                                              163.5-164.5           301  6      H                                                                                      ##STR391##                                                                               ##STR392##                                                                              CH.sub.3   Colorless needle-like                                                          crystals                                                                              146-149               302  6                                                                                      ##STR393##                                                                           (CH.sub.2).sub.3                                                                          ##STR394##                                                                              CH.sub.3   Colorless needle-like                                                          crystals                                                                              107.5-108.5           303  6      H      (CH.sub.2).sub.3                                                                          ##STR395##                                                                              H          Colorless crystals                                                                    202.5-206             304  6      CH.sub.3                                                                              (CH.sub.2).sub.3                                                                          ##STR396##                                                                              CH.sub.3   Colorless needle-like                                                          crystals                                                                              118.5-119.5           305  6      H      (CH.sub.2).sub.3                                                                          ##STR397##                                                                               ##STR398##                                                                               Colorless needle-like                                                          crystals                                                                              185.5-187             306  5      CH.sub.3                                                                               ##STR399##                                                                               ##STR400##                                                                              H          Colorless needle-like                                                          crystals                                                                              189-190               307  5      H      CH.sub.2                                                                                  ##STR401##                                                                              H          Colorless needle-like                                                          crystals                                                                              202-204.5             __________________________________________________________________________

                                      TABLE 22                                     __________________________________________________________________________      ##STR402##                                                                     Exam- ple No.                                                                     Position of the sub- stituted side- chain                                            Bonding at 3- and 4- posi- tions                                                    R.sup.1                                                                           (R.sup.2).sub.m                                                                      Posi- tion(s) of the sub- stituted R.sup.2                                           ##STR403##                                                                              R.sup.4  R.sup.5                                                                              Crystal form                                                                        Melting point                                                                 (°C.)         __________________________________________________________________________     308   5  Single bond                                                                         H  Br       8  CH.sub.2                                                                                 ##STR404##                                                                             H     Colorless needle-                                                              like crystals                                                                       212- 212.5           309   5  Single bond                                                                         H  (I).sub.2                                                                               6 8                                                                               (CH.sub.2).sub.3                                                                         ##STR405##                                                                             (CH.sub.2).sub.3 CH.sub.3                                                            Colorless needle-                                                              like crystals                                                                       109.5- 110.5         310   8  Single bond                                                                         H  (Cl).sub.3                                                                              5 6 7                                                                             (CH.sub.2).sub.3                                                                         ##STR406##                                                                             CH.sub.3                                                                             Colorless needle-                                                              like crystals                                                                       131- 132.5           311   5  Single bond                                                                         H  (Cl).sub.2                                                                              6 8                                                                               (CH.sub.2).sub.3                                                                         ##STR407##                                                                             C.sub.2 H.sub.5                                                                      Colorless rhombic                                                              crystals                                                                            130- 132             312   5  Single bond                                                                         H                                                                                  ##STR408##                                                                             8  (CH.sub.2).sub.3                                                                         ##STR409##                                                                             CH.sub.3                                                                             Colorless prism-                                                               like crystals                                                                       106.5- 110           313   6  Double bond                                                                         H  Cl       5  CH.sub. 2                                                                                ##STR410##                                                                             H     Colorless needle-                                                              like crystals                                                                       225- 226             314   6  Double bond                                                                         H  Cl       5  CH.sub.2                                                                                 ##STR411##                                                                             H     Colorless needle-                                                              like crystals                                                                       311.5- 313                                                                     (decom- posed)       315   6  Double bond                                                                         H  Cl       5  (CH.sub.2).sub.3                                                                         ##STR412##                                                                             CH.sub.3                                                                             Colorless needle-                                                              like crystals                                                                       191.5- 193           316   6  Double bond                                                                         CH.sub.3                                                                          Cl       5  (CH.sub.2).sub.3                                                                         ##STR413##                                                                             CH.sub.3                                                                             Pale- yellowish                                                                needle- like                                                                   crystals                                                                            137- 138             __________________________________________________________________________

EXAMPLE 317

3.2 Grams of 6-hydroxy-3,4-dihydrocarbostyril, 0.9 g of potassium hydroxide, 3.2 g of sodium iodide and 5.0 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine are added to 50 ml of dimethylsulfoxide, and the mixture is agitated at 70° to 80° C. for 4.5 hours. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The thus obtained crude crystals are then recrystallized from benzene-petroluem ether to obtain 2.9 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needlelike crystals with melting point of 144°-146° C.

EXAMPLE 318

1.6 Grams of 5-hydroxy-3,4-dihydrocarbostyril, 0.8 g of pyridine, 1.8 g of potassium iodide and 2.8 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine are added to 30 ml of dioxane, and the mixture is refluxed under agitation for 12 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out. The crude crystals are dissolved in 50 ml of chloroform and the organic layer is washed with 1 N sodium hydroxide (50 ml×2), water and then, dried with anhydrous sodium sulfate, followed by removal of the solvent by distillation, and the resultant residue is recrystallized from ethyl acetate to obtain 0.8 g of 5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless prism-like crystals with melting point of 133°-134° C.

EXAMPLE 319

1.6 Grams of 6-hydroxycarbostyril, 0.7 g of sodium ethylate, 1.6 g of sodium iodide and 2.4 g of N-methyl-N-(4-chlorobutyryl)aniline are added to 30 ml of ethanol and refluxed under agitation for 6 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from chloroform-petroleum ether to obtain 1.3 g of 6-[3-(N-methylanilinocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 187°-189° C.

EXAMPLE 320

0.5 Gram of metallic sodium is dissolved in 50 ml of methanol under ice cooling, and to this solution is added 3.2 g of 6-hydroxy-3,4-dihydrocarbostyril, 3.2 g of sodium iodide and 4.6 g of N-(4-chlorobutyryl)cyclohexylamine, followed by 5-hour refluxing under agitation. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from methanol to obtain 3.1 g of 6-[3-(N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 220°-221° C.

EXAMPLE 321

1.6 Grams of 6-hydroxycarbostyril, 1.4 g of K₂ CO₃, 1.6 g of sodium iodide and 2.5 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine are added to 30 ml of DMF and the mixture is agitated at 70° to 80° C. for 4 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from chloroformethanol to obtain 1.5 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 184.5°-186° C.

EXAMPLES 322-384

The compounds shown in Table 23 below are obtained according to the procedure of Examples 317-321.

                                      TABLE 23                                     __________________________________________________________________________      ##STR414##                                                                         Position of the                                                                        Bonding at                       Melting                          Example                                                                             substituted                                                                            3- and 4-                  Crystal                                                                              point                            No.  side-chain                                                                             positions                                                                            n'                                                                               R.sup.4    R.sup.5 form  (°C.)                     __________________________________________________________________________     322  5       Single bond                                                                          3                                                                                 ##STR415##                                                                               CH.sub.2 CHCH.sub.2                                                                    Colorless needle-like crystals                                                       116.5- 118                       323  5       Single bond                                                                          3                                                                                 ##STR416##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       179.5- 180.5                     324  5       Single bond                                                                          3                                                                                 ##STR417##                                                                               H       Colorless needle-like crystals                                                       211- 212.5                       325  5       Double bond                                                                          3                                                                                 ##STR418##                                                                               CH.sub.3                                                                               Colorless needle-like crystals                                                       172.5- 174                       326  5       Double bond                                                                          3                                                                                 ##STR419##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       216.5- 218.5                     327  5       Single bond                                                                          4                                                                                 ##STR420##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-like crystals                                                       121- 123.5                       328  6       Single bond                                                                          1                                                                                 ##STR421##                                                                               C.sub.2 H.sub.5                                                                        Colorless rhombic crystals                                                           133- 135                         329  6       Single bond                                                                          1                                                                                 ##STR422##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless rhombic crystals                                                           111- 113                         330  6       Single bond                                                                          1                                                                                 ##STR423##                                                                               H       Colorless needle-like crystals                                                       197- 198                         331  6       Single bond                                                                          1                                                                                 ##STR424##                                                                               H       Colorless needle-like crystals                                                       191.5- 192.5                     332  6       Single bond                                                                          3                                                                                 ##STR425##                                                                               CH.sub.2 CHCH.sub. 2                                                                   Colorless needle-like crystals                                                       105- 107                         333  6       Single bond                                                                          3                                                                                 ##STR426##                                                                                ##STR427##                                                                            Colorless needle-like crystals                                                       182- 184                         334  6       Single bond                                                                          3                                                                                 ##STR428##                                                                               H       Colorless plate-like crystals                                                        186- 187                         335  6       Single bond                                                                          3                                                                                 ##STR429##                                                                               CH.sub.3                                                                               Colorless needle-like crystals                                                       129.5- 131.5                     336  6       Single bond                                                                          3                                                                                 ##STR430##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless rhombic crystals                                                           108- 110                         337  6       Single bond                                                                          3                                                                                 ##STR431##                                                                                ##STR432##                                                                            Colorless needle-like crystals                                                       201- 205                         338  6       Single bond                                                                          3                                                                                 ##STR433##                                                                               H       Colorless needle-like crystals                                                       186- 187.5                       339  6       Single bond                                                                          3                                                                                 ##STR434##                                                                               H       Colorless needle-like crystals                                                       265-  266 (decom- posed)         340  6       Single bond                                                                          3                                                                                 ##STR435##                                                                               H       Colorless rhombic crystals                                                           214- 215 (decom- posed)          341  6       Single bond                                                                          4                                                                                 ##STR436##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-like crystals                                                       109.5- 111.5                     342  6       Single bond                                                                          4                                                                                 ##STR437##                                                                               CH.sub.3                                                                               Colorless rhombic crystals                                                           129.5- 131                       343  6       Single bond                                                                          4                                                                                 ##STR438##                                                                               H       Colorless needle-like crystals                                                       183- 184.5                       344  6       Double bond                                                                          3                                                                                 ##STR439##                                                                               H       Colorless needle-like crystals                                                       251- 252                         345  6       Double bond                                                                          3                                                                                 ##STR440##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       167.5- 169                       346  6       Double bond                                                                          3                                                                                 ##STR441##                                                                                ##STR442##                                                                            Colorless needle-like crystals                                                       174- 175                         347  6       Double bond                                                                          3                                                                                 ##STR443##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-like crystals                                                       159- 160                         348  6       Double bond                                                                          3                                                                                 ##STR444##                                                                                ##STR445##                                                                            Colorless needle-like crystals                                                       228.5- 230.5                     349  6       Double bond                                                                          3                                                                                 ##STR446##                                                                                ##STR447##                                                                            Colorless needle-like crystals                                                       180- 181.5                       350  6       Double bond                                                                          3                                                                                 ##STR448##                                                                               H       Colorless needle-like crystals                                                       251.5- 253                       351  6       Double bond                                                                          3                                                                                 ##STR449##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       115.5- 117                       352  6       Double bond                                                                          3                                                                                 ##STR450##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-like crystals                                                       159- 160.5                       353  6       Double bond                                                                          3                                                                                 ##STR451##                                                                               CH.sub.3                                                                               Colorless needle-like crystals                                                       143- 143.5                       354  6       Double bond                                                                          3                                                                                 ##STR452##                                                                               H       Colorless needle-like crystals                                                       222.5- 224                       355  6       Double bond                                                                          3                                                                                 ##STR453##                                                                               H       Colorless needle-like crystals                                                       236- 237                         356  6       Double bond                                                                          4                                                                                 ##STR454##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-like crystals                                                       151- 153.5                       357  5       Single bond                                                                          3                                                                                 ##STR455##                                                                               H       Colorless needle-like crystals                                                       241.5- 242                       358  5       Single bond                                                                          3                                                                                 ##STR456##                                                                               H       Colorless needle-like crystals                                                       206- 207                         359  5       Single bond                                                                          6                                                                                 ##STR457##                                                                               C.sub.2 H.sub.5                                                                        Colorless plate-like crystals                                                        129- 131.5                       360  5       Double bond                                                                          3                                                                                 ##STR458##                                                                               CH.sub.3                                                                               Colorless flake crystals                                                             223- 225 (decom- posed)          361  5       Double bond                                                                          3                                                                                 ##STR459##                                                                               H       Colorless plate-like crystals                                                        171- 175                         362  5       Double bond                                                                          3                                                                                 ##STR460##                                                                               H       Colorless needle-like crystals                                                       241- 242 (decom- posed)          363  6       Single bond                                                                          1                                                                                 ##STR461##                                                                               H       Colorless needle-like crystals                                                       202.5- 204                       364  6       Double bond                                                                          1                                                                                 ##STR462##                                                                               CH.sub.3                                                                               Pale- yellowish needle-like                                                    crystals                                                                             131- 133.5                       365  6       Single bond                                                                          3                                                                                 ##STR463##                                                                               CH.sub.3                                                                               Colorless needle-like crystals                                                       108- 112                         366  6       Single bond                                                                          3                                                                                 ##STR464##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       110- 111.5                       367  6       Double bond                                                                          3                                                                                 ##STR465##                                                                               H       Colorless needle-like crystals                                                       209- 210                         368  6       Double bond                                                                          3                                                                                 ##STR466##                                                                               CH.sub.2 CH.sub.2 CH.sub.3                                                             Colorless needle-like crystals                                                       182- 184.5                       369  6       Double bond                                                                          4                                                                                 ##STR467##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless needle-like crystals                                                       151- 153.5                       370  6       Single bond                                                                          6                                                                                 ##STR468##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       111- 112.5                       371  6       Single bond                                                                          6                                                                                 ##STR469##                                                                               CH.sub.2 CH.sub.2 CH.sub.3                                                             Colorless needle-like crystals                                                       90.5- 92                         372  7       Single bond                                                                          3                                                                                 ##STR470##                                                                               CH.sub.3                                                                               Colorless rhombic crystals                                                           114.5- 117                       373  8       Double bond                                                                          1                                                                                 ##STR471##                                                                               H       Colorless needle-like crystals                                                       235- 236                         374  8       Double bond                                                                          1                                                                                 ##STR472##                                                                               CH.sub.3                                                                               Colorless rhombic crystals                                                           176- 178                         375  8       Single bond                                                                          3                                                                                 ##STR473##                                                                               CH.sub.3                                                                               Colorless rhombic crystals                                                           141- 142                         376  8       Single bond                                                                          3                                                                                 ##STR474##                                                                               H       Colorless rhombic crystals                                                           193- 195.5                       377  6       Double bond                                                                          3                                                                                 ##STR475##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       150- 152                         378  6       Double bond                                                                          3                                                                                 ##STR476##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       158- 160                         379  6       Double bond                                                                          3                                                                                 ##STR477##                                                                               C.sub.2 H.sub.5                                                                        Colorless needle-like crystals                                                       145- 147                         380  6       Double bond                                                                          3                                                                                 ##STR478##                                                                               C.sub.2 H.sub.5                                                                        Colorless  needle-like crystals                                                      143- 144.5                       381  6       Double bond                                                                          3                                                                                 ##STR479##                                                                               (CH.sub.2).sub.4 CH.sub.3                                                              Colorless needle-like crystals                                                       156.5- 157.5                     382  6       Double bond                                                                          3                                                                                 ##STR480##                                                                               (CH.sub.2).sub.5 CH.sub.3                                                              Colorless needle-like crystals                                                       129- 132                         383  6       Double bond                                                                          3                                                                                 ##STR481##                                                                               (CH.sub.2).sub.7 CH.sub.3                                                              Colorless crystals                                                                   100- 103                         384  6       Single bond                                                                          3                                                                                 ##STR482##                                                                               (CH.sub.2).sub.3 CH.sub.3                                                              Colorless rhombic crystals                                                           142- 143.5                       __________________________________________________________________________

EXAMPLE 385

1.6 Grams of 6-hydroxy-3,4-dihydrcarbostyril, 1.4 g of K₂ CO₃, 1.6 g of sodium iodide and 2.7 g of N-(4-chlorobutyryl)-2-cyclopentyl-1-methylethylamine are added to 30 ml of dimethylformamide, and the mixture is agitated at 70° to 80° C. for 3.5 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crystals are recrystallized from chloroform-petroleum ether to obtain 3.4 g of 6-{3-[N-(2-cyclopentyl-1-methylethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 138°-139.5° C.

EXAMPLES 386-388

The compounds of Table 24 below are obtained in the same way as Example 385.

                  TABLE 24                                                         ______________________________________                                          ##STR483##                                                                    Ex-                                                                            am-  Bonding at                         Melting                                ple  3- and 4-                  Crystal point                                  No.  positions n'    R.sup.4    form    (°C.)                           ______________________________________                                         386  Single bond                                                                              3                                                                                     ##STR484##                                                                               Colorless needle-like crystals                                                         170-172                                387  Single bond                                                                              1                                                                                     ##STR485##                                                                               Colorless needle-like crystals                                                         174.5-176                              388  Double bond                                                                              3                                                                                     ##STR486##                                                                               Colorless needle-like crystals                                                         173-175                                ______________________________________                                    

EXAMPLE 389

1.75 Grams of 1-methyl-6-hydroxycarbostyril, 1.8 g of K₂ CO₃ and 0.5 g of KI are added to 50 ml of DMF, and then 2.8 g of N-methyl-N(4-chlorobutyryl)cyclohexylamine is added gradually dropwise to this solution at 60° to 70° C. under agitation, followed by additional 4-hour agitation at the same temperature and removal of the solvent by distillation. The residue is dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid, a 1% aqueous NaOH solution and water and then dried with anhydrous Na₂ SO₄. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is crystallized from petroleum ether. The obtained crystals are recrystallized from benzene-ligroin to produce 0.6 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)-propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 118.5°-119.5° C.

EXAMPLE 390

3.4 Grams of 1-methyl-6-hydroxy-3,4-dihydrocarbostyril, 0.9 g of potassium hydroxide, 3.2 g of sodium iodide and 5.0 g of N-methyl-N-(4-chlorobutyryl)-cyclohexylamine are added to 50 ml of dimethylsulfoxide and agitated at 70° to 80° C. for 4.5 hours. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from ligroin to obtain 3.1 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.

EXAMPLE 391

1.6 Grams of 5-hydroxy-3,4-dihydrocarbostyril, 0.8 g of pyridine, 1.8 g of potassium iodide and 3.1 g of N-ethyl-N-(4-chloro-3-methylbutyryl)cyclohexylamine are added to 30 ml of dioxane and the mixture is refluxed under agitation for 12 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out. The crude crystals are dissolved in 50 ml of chloroform and the organic layer is washed with 1 N NaOH (50 ml×2), water and dried with anhydrous Na₂ SO₄, followed by removal of the solvent by distillation. The resultant residue is recrystallized from ligroin-benzene to produce 0.9 g of 5-[3-(N-ethyl-N-cyclohexylamiocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 114°-115.5° C.

EXAMPLE 392

0.5 Gram of metallic sodium is dissolved in 50 ml of methanol under ice cooling, followed by addition thereto of 3.4 g of 1-methyl-6-hydroxy-3,4-dihydrocarbostyril, 3.2 g of sodium iodide and 5.0 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine and 4.5-hour reflux under agitation. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from ligroin to produce 2.9 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.

EXAMPLE 393

1.6 Grams of 6-hydroxycarbostyril, 0.7 g of sodium ethylate, 1.6 g of sodium iodide and 3.3 g of N-ethyl-N-(4-chloro-3-methylbutyryl)-2-methylcyclohexylamine are added to 30 ml of ethanol and the mixture is refluxed under agitation for 5 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from benzene-ligroin to obtain 1.4 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril with melting point of 146°-149° C.

EXAMPLE 394

1.6 Grams of 6-hydroxycarbostyril, 1.4 g of K₂ CO₃, 1.6 g of sodium iodide and 3.3 g of N-ethyl-N-(4-chloro-3-methylbutyryl)-2-methylcyclohexylamine are added to 30 ml of DMF and agitated at 70° to 80° C. for 4.5 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from benzene-ligroin to produce 1.4 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril with melting point of 146°-149° C.

EXAMPLES 395-469

The compounds in Tables 25-27 below are obtained from the procedures of Examples 389-394. The respective compounds in these tables are expressed by the symbols given in the general formulae (1-1), (1-2) and (1-3), respectively.

                                      TABLE 25                                     __________________________________________________________________________      ##STR487##                                                 (1-1)               No.Example                                                                         Position of the sub- stituted side-chain                                              R.sup.1                                                                                ##STR488##                                                                              R.sup.4       R.sup.5  formCrystal                                                                          (°C.)poin                                                              tMelting              __________________________________________________________________________     395  5     H       CH.sub.2                                                                                 ##STR489##   H        Pale- yellowish                                                                crystals                                                                             286- 288.5                                                                     (decom- posed)        396  5     CH.sub.3                                                                                "                                                                                       ##STR490##   H        Colorless needle-like                                                          crystals                                                                             186-  187             397  5     CHCH.sub.2CH.sub.2                                                                      ##STR491##                                                                              ##STR492##   H        Colorless needle-like                                                          crystals                                                                             141.5- 142            398  5     H        "                                                                                       ##STR493##   H        Colorless needle-like                                                          crystals                                                                             186- 189              399  5     H        "                                                                                       ##STR494##   H        Colorless flake-like                                                           crystals                                                                             211- 212              400  5     H                                                                                       ##STR495##                                                                              ##STR496##   C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             159- 161              401  5     H       (CH.sub.2).sub.2                                                                         ##STR497##   H        Colorless needle-like                                                          crystals                                                                             190.5- 192            402  5     H       (CH.sub.2).sub.3                                                                         ##STR498##   H        Colorless needle-like                                                          crystals                                                                             207- 208.5            403  5     H         "                                                                                      ##STR499##   H        Colorless needle-like                                                          crystals                                                                             270- 274 (decom-                                                               osed)                 404  5     H        "                                                                                       ##STR500##   H        Colorless needle-like                                                          crystals                                                                             212- 213              405  5     H        "                                                                                       ##STR501##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             169- 172              406  5     C.sub.2 H.sub.5                                                                         "                                                                                       ##STR502##   H        Colorless needle-like                                                          crystals                                                                             122.5- 124            407  5      "       "                                                                                       ##STR503##   H        Colorless needle-like                                                          crystals                                                                             141.5- 143            408  5     H       (CH.sub.2).sub.6                                                                         ##STR504##                                                                                   ##STR505##                                                                             Colorless needle-like                                                          crystals                                                                             49- 52                409  5     H                                                                                       ##STR506##                                                                              ##STR507##   H        Colorless needle-like                                                          crystals                                                                             181- 182.5            410  6     H       (CH.sub.2).sub.3                                                                         ##STR508##   H        Colorless needle-like                                                          crystals                                                                             211.5- 213            411  6     H        "                                                                                       ##STR509##   CH.sub.3 Colorless needle-like                                                          crystals                                                                             129.5- 132.5          412  6     H        "                                                                                       ##STR510##    "       Colorless crystals                                                                   31- 35                413  6     CH.sub.2 CHCH.sub.2                                                                    (CH.sub.2).sub.6                                                                         ##STR511##   H        Colorless needle-like                                                          crystals                                                                             104- 105.5            414  7     H                                                                                       ##STR512##                                                                              ##STR513##   H        Colorless needle-like                                                          crystals                                                                             182.5- 183            415  5     H       (CH.sub.2).sub.3                                                                         ##STR514##   H        Colorless needle-like                                                          crystals                                                                             236- 239 (decom-                                                               osed)                 416  5     H                                                                                       ##STR515##                                                                              ##STR516##   H        Colorless needle-like                                                          crystals                                                                             156- 158              417  6     H       (CH.sub.2).sub.3                                                                         ##STR517##                                                                                   ##STR518##                                                                             Colorless needle-like                                                          crystals                                                                             160- 161              418  6     H        "                                                                                       ##STR519##                                                                                   ##STR520##                                                                             Colorless needle-like                                                          crystals                                                                             166- 168              419  6     H        "                                                                                       ##STR521##   H        Colorless needle-like                                                          crystals                                                                             298- 299 (decom-                                                               osed)                 420  6     H        "                                                                                       ##STR522##   H        Colorless crystals                                                                   235- 238              __________________________________________________________________________

                                      TABLE 26                                     __________________________________________________________________________      ##STR523##                                                 (1-2)               No.Example                                                                         Position of the sub- stituted side-chain                                              R.sup.1                                                                               ##STR524##                                                                              R.sup.4        R.sup.5  formCrystal                                                                          (°C.)poin                                                              tMelting              __________________________________________________________________________     421  5     H      CH.sub.2                                                                                 ##STR525##    H        Yellowish- plate-like                                                          crystals                                                                             183- 186              422  5     H       "                                                                                       ##STR526##    H        Colorless plate-like                                                           crystals                                                                             181.5- 185            423  5     H       "                                                                                       ##STR527##    H        Colorless needle-like                                                          crystals                                                                             202- 204.5            424  5     CH.sub.3                                                                               ##STR528##                                                                              ##STR529##    H        Colorless needle-like                                                          crystals                                                                             189- 190              425  5     H      (CH.sub.2).sub.3                                                                         ##STR530##    H        Colorless flake-like                                                           crystals                                                                             168.5- 171            426  5     H       "                                                                                       ##STR531##    H        Colorless flake-like                                                           crystals                                                                             236.5- 237                                                                     (decom- posed)        427  6     H                                                                                      ##STR532##                                                                              ##STR533##    CH.sub.3 Colorless plate-like                                                           crystals                                                                             172- 176              428  6     H      (CH.sub.2).sub.3                                                                         ##STR534##    H        Colorless needle-like                                                          crystals                                                                             255- 257              429  6                                                                                     ##STR535##                                                                            "                                                                                       ##STR536##    CH.sub.3 Colorless needle-like                                                          crystals                                                                             107.5- 108.5          430  6     H       "                                                                                       ##STR537##    CH.sub.3 Colorless needle-like                                                          crystals                                                                             199- 201              431  6     H       "                                                                                       ##STR538##    H        Colorless crystals                                                                   202.5- 206            432  6     H       "                                                                                       ##STR539##    H        Colorless needle-like                                                          crystals                                                                             184- 185              433  6     H       "                                                                                       ##STR540##                                                                                    ##STR541##                                                                             Colorless needle-like                                                          crystals                                                                             185.5- 187            434  6     H       "                                                                                       ##STR542##    CH.sub.3 Colorless crystals                                                                   187- 190              435  6     H       "                                                                                       ##STR543##    C.sub.2 H.sub.5                                                                         Colorless needle-like                                                          crystals                                                                             150.5- 153            436  6     H       "                                                                                       ##STR544##                                                                                    ##STR545##                                                                             Colorless needle-like                                                          crystals                                                                             163.5- 164.5          437  6     H                                                                                      ##STR546##                                                                              ##STR547##    CH.sub.2 CH.sub.2 CH.sub.3                                                              Colorless plate-like                                                           crystals                                                                             134.5- 137.5          438  8     H      CH.sub.2                                                                                 ##STR548##    H        Colorless needle-like                                                          crystals                                                                             192.5- 193.5          439  6     H      (CH.sub.2).sub.3                                                                         ##STR549##    H        Colorless needle-like                                                          crystals                                                                             122- 124              440  6     H       "                                                                                       ##STR550##    CH.sub.3 Colorless needle-like                                                          crystals                                                                             137- 140              441  6     H       "                                                                                       ##STR551##                                                                                    ##STR552##                                                                             Colorless crystals                                                                   78- 81                442  6     H       "                                                                                       ##STR553##    H        Pale- yellowish                                                                crystals                                                                             157- 160              443  6     H       "                                                                                       ##STR554##    H        Colorless needle-like                                                          crystals                                                                             105- 109              444  6     H                                                                                      ##STR555##                                                                              ##STR556##    CH.sub.3 Colorless needle-like                                                          crystals                                                                             180- 182              445  6     H                                                                                      ##STR557##                                                                              ##STR558##    H        Colorless needle-like                                                          crystals                                                                             201- 203              446  6     H      (CH.sub.2).sub.3                                                                         ##STR559##    CH.sub.3 Colorless needle-like                                                          crystals                                                                             127.5- 129.5          447  6     H       "                                                                                       ##STR560##    C.sub.2 H.sub.5                                                                         Colorless rhombic                                                              crystals                                                                             105- 107              448  6     H       "                                                                                       ##STR561##    CH.sub.3 Colorless needle-like                                                          rystals                                                                              166.5- 168            449  6     H       "                                                                                       ##STR562##    (CH.sub.2).sub.7 CH.sub.3                                                               Colorless needle-like                                                          crystals                                                                             127- 128.5            450  6     H       "                                                                                       ##STR563##    "        Colorless crystals                                                                   63.5- 66.0            451  6     H       "                                                                                       ##STR564##     "       Colorless crystals                                                                   86.0- 89.5            __________________________________________________________________________

                                      TABLE 27                                     __________________________________________________________________________      ##STR565##                                                 (1-3)               No.pleam-Ex-                                                                     Posi- tion of the sub- stituted side- chain                                         tionsposi-and 4-at 3-ingBond-                                                      R.sup.1                                                                           (R.sup.2).sub.m                                                                      Posi- tions of the sub- stituted R.sup.2 group                                      ##STR566##                                                                              R.sup.4     R.sup.5                                                                               formCrystal                                                                          (°C.)po                                                                intingMelt-         __________________________________________________________________________     452                                                                               5   Single bond                                                                        H  Br     8    CH.sub.2                                                                              ##STR567##   H      Colorless needle-                                                              like crystals                                                                        212- 212.5          453                                                                               5   Single bond                                                                        H  Br     "    "                                                                                     ##STR568##   H      Colorless needle-                                                              like crystals                                                                        258- 259.5          454                                                                               5   Single bond                                                                        H  Br     "   (CH.sub.2).sub.3                                                                       ##STR569##   CH.sub.3                                                                              Colorless needle-                                                              like crystals                                                                        134- 135            455                                                                               5   Single bond                                                                        H  Br     "    "                                                                                     ##STR570##   H      Colorless needle-                                                              like crystals                                                                        260.5- 261                                                                     (decom-                                                                        posed)              456                                                                               5   Single bond                                                                        H  I      "    "                                                                                     ##STR571##   H      Colorless needle-                                                              like crystals                                                                        190- 191            457                                                                               5   Single bond                                                                        H  (I).sub.2                                                                             6 8  "                                                                                     ##STR572##   (CH.sub.2).sub.3 CH.sub.3                                                             Colorless needle-                                                              like crystals                                                                        109.5- 110.5        458                                                                               5   Single bond                                                                        H  (Cl).sub.2                                                                            6 8  "                                                                                     ##STR573##   C.sub.2 H.sub.5                                                                       Colorless rhombic                                                              crystals                                                                             130- 132            459                                                                               5   Single bond                                                                        H  (Cl).sub.2                                                                            6 8  "                                                                                     ##STR574##   H      Colorless rhombic                                                              crystals                                                                             270- 271                                                                       (decom-                                                                        posed)              460                                                                               6   Double bond                                                                        H  Cl     5   CH.sub.2                                                                               ##STR575##   H      Colorless rhombic                                                              crystals                                                                             225- 226            461                                                                               6   Double bond                                                                        H  Cl     "    "                                                                                     ##STR576##   H      Colorless needle-                                                              like crystals                                                                        311.5- 313                                                                     (decom-                                                                        posed)              462                                                                               6   Double bond                                                                        H  Cl     "   (CH.sub.2).sub.3                                                                       ##STR577##   CH.sub.3                                                                              Colorless needle-                                                              like crystals                                                                        179- 180.5          463                                                                               6   Double bond                                                                        H  Cl     "    "                                                                                     ##STR578##    "     Colorless needle-                                                              like crystals                                                                        191.5- 193          464                                                                               6   Double bond                                                                        CH.sub.3                                                                          Cl     "    "                                                                                     ##STR579##    "     Pale- yellowish                                                                needle- like                                                                   crystals                                                                             137- 138            465                                                                               6   Double bond                                                                        H  Cl     "    "                                                                                     ##STR580##   C.sub.2 H.sub.5                                                                       Colorless needle-                                                              like crystals                                                                        134.5- 136          466                                                                               8   Single bond                                                                        H  (Cl).sub.3                                                                            5 6 7                                                                               "                                                                                     ##STR581##   CH.sub.3                                                                              Colorless needle-                                                              like crystals                                                                        131- 132.5          467                                                                               6   Double bond                                                                        H  Cl     5    "                                                                                     ##STR582##   (CH.sub.2).sub.3 CH.sub.3                                                             Colorless needle-                                                              like crystals                                                                        178.5- 179.5        468                                                                               5   Single bond                                                                        H                                                                                  ##STR583##                                                                           8    "                                                                                     ##STR584##   CH.sub.3                                                                              Colorless prism-                                                               like crystals                                                                        106.5- 110          469                                                                               5   Single bond                                                                        H   "     "    "                                                                                     ##STR585##   (CH.sub.2).sub.2 CH.sub.3                                                             Colorless plate-                                                               like crystals                                                                        88- 90.5            __________________________________________________________________________

EXAMPLE 470

The process of Example 394 is repeated by using a suitable starting material to obtain 6-{3-[N-benzyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril. This compound is identified by the following physicochemical properties.

State: Colorless oil

Silica gel thin-layer chromatography: (Silica gel: "Silica-Gel 60 F-254" manufactured by Merck & Co., Inc.); Developing solvent: 8/1 (V/V) a mixture of chloroform-methanol Rf=0.65

Elemental analysis: Calcd. for C₃₀ H₃₄ N₂ O₅ : C, 71.69%; H, 6.82%; N, 5.57%; Found: C, 71.84%; H, 6.75%; N, 5.29%

Nuclear magnetic resonance spectrum (NMR): δCDCl₃ =1.9-3.1 ppm (10H, m), 3.4 ppm (2H, t), 3.7-4.0 ppm (8H, m), 4.4 ppm (2H, d), 6.4-6.7 ppm (6H, m), 6.9-7.3 ppm (7H, m), 9.3 ppm (1H, br.)

The 6.9-7.3 ppm signal overlaps with the CHCl₃ proton signal.

Infrared absorption spectrum (IR): ν_(max) ^(film) (cm⁻¹)=3220, 3002, 2940, 2840, 1670, 1638, 1595, 1500, 1450, 1360, 1240, 1157, 1013, 960, 850, 800, 740

EXAMPLE 471

3.3 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)-aminocarbonyl]-2-methylpropoxy}-3,4-dihydrocarbostyril and 3.4 g of 90% DDQ are added to 100 ml of dioxane and this mixture is refluxed for 9.5 hours and then cooled. After the reaction, the solvent is distilled off and the obtained residue is dissolved in chloroform and the organic layer is washed with aqueous saturated NaHCO₃ solution, and with water, dried with anhydrous Na₂ SO₄ and then treated with an active charcoal treatment. After distilling off the solvent, the resultant residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 10:1 chloroform-methanol (V/V)) and the crude crystals are recrystallized from benzene-ligron to produce 1.2 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals. Melting point: 146°-149° C.

EXAMPLE 472

To a solution of 2.8 g of 1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in 50 ml of methanol is added 0.1 g of palladium black, and the mixture is reacted at 50° C. under hydrogen pressure of 2.5 atm. for 8 hours. After the reaction, the catalyst is filtered out and the filtrate is concentrated and evaporated to dryness. The residue is recrystallized from ligroin to obtain 1.9 g of 1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.

EXAMPLE 473

To a solution of 1.7 g of 6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in 50 ml of DMF is added 0.3 g of sodium hydroxide at room temperature under agitation. After the end of hydrogen generation, 1 ml of methyl iodide is added dropwise to the solution and the mixture is agitated at room temperature for 3 hours. After the reaction, the solvent is distilled off under reduced pressure and the residue is dissolved in 200 ml of chloroform. The chloroform layer is washed with an aqueous K₂ CO₃ solution and water and then dried with anhydrous Na₂ SO₄. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin to obtain 0.9 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C. 

What is claimed is:
 1. A compound of the formula, ##STR586## wherein R¹ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl or phenyl C₁₋₄ alkyl; R² is hydrogen, halogen, hydroxy or phenyl C₁₋₄ alkoxy; R³ is hydrogen, hydroxy or C₁₋₄ alkyl; R⁴ is phenyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl C₁₋₄ alkyl or 2-(3,4-dimethoxyphenyl)ethyl or phenyl or C₃₋₈ cycloalkyl substituted by no more than two groups selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, C₁₋₄ alkanoylamino, C₁₋₄ alkanoyloxy, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkanoyl, C₁₋₄ alkylcarbamoyl, C₁₋₄ alkylamine, nitro, carboxy, hydroxyl, amninosulfonyl, carbamoyl, and amino; R⁵ is hydrogen, C₁₋₈ alkyl, C₂₋₄ alkenyl, phenyl, C₃₋₈ cycloalkyl, phenyl C₁₋₄ alkyl or C₃₋₈ cycloalkyl C₁₋₄ alkyl or sustituted phenyl C₁₋₄ alkyl substituted in the phenyl group by no more than two C₁₋ 4 alkoxy groups; m is an integer of 1 to 3; and l and n, which can be the same or different, are 0 or an integer of 1 to 7 such that the sum of l and n does not exceed
 7. 2. A compound according to claim 1, wherein R⁴ is a substituted or an unsubstituted C₃₋₈ cycloalkyl group.
 3. A compound according to claim 2, wherein R⁵ is C₁₋₈ alkyl.
 4. A compound according to claim 2, wherein R⁵ is C₂₋₄ alkenyl.
 5. A compound according to claim 2, wherein R⁵ is phenyl.
 6. A compound according to claim 2, wherein R⁵ is C₃₋₈ cycloalkyl.
 7. A compound according to claim 2, wherein R⁵ is a substituted or an unsubstituted phenyl C₁₋₄ alkyl group.
 8. A compound according to claim 2, wherein R⁵ is C₃₋₈ cycloalkyl C₁₋₄ alkyl.
 9. A compound according to claim 2, wherein R⁵ is hydrogen.
 10. A compound according to claim 2, wherein R¹ is hydrogen.
 11. A compound according to claim 2, wherein R² is hydrogen.
 12. A compound according to claim 2, wherein R³ is hydrogen.
 13. A compound according to claim 2, of the formula (1).
 14. A compound according to claim 2, of the formula, ##STR587##
 15. A compound according to claim 14, of the formula (3).
 16. A compound according to claim 14, of the formula (4).
 17. A compound according to claim 2, of the formula, ##STR588##
 18. A compound according to claim 17, of the formula (5).
 19. A compound according to claim 17, of the formula (6).
 20. A compound according to claim 3, of the formula, ##STR589##
 21. A compound according to claim 20, wherein each of R₁, R₂ and R₃ is hydrogen.
 22. A compound according to claim 21, of the formula (7).
 23. 6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril.
 24. 6-[3-(N-Ethyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril.
 25. 6-[3-(N-Butyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril.
 26. 6-[3-(N-Ethyl-N-cyclopropylaminocarbonyl)-propoxy]carbostyril.
 27. 6-[3-(N-Ethyl-N-cyclopentylaminocarbonyl)-propoxy]carbostyril.
 28. 6-[3-(N-Ethyl-N-cycloheptylaminocarbonyl)-propoxy]carbostyril.
 29. 6-[3-(N-Ethyl-N-cyclooctylaminocarbonyl)propoxy]-carbostyril.
 30. 6-[3-(N-Pentyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril.
 31. 6-[3-(N-Hexyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril.
 32. 6-[3-(N-Octyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril.
 33. 6-[3-(N-Heptyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril.
 34. 6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-2-methylpropoxy]carbostyril.
 35. 6-{3-[N-(2-3',4'-Dimethoxyphenylethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril. 